Pyrrolidine gpr40 modulators

ABSTRACT

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.15/840,198, filed Dec. 13, 2017, which is a continuation application ofU.S. Ser. No. 14/705,524, filed May 6, 2015, now U.S. Pat. No.9,873,679, which claims priority to U.S. Provisional Application Ser.No. 61/989,651, filed May 7, 2014; the contents of which are hereinincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention provides novel carboxylic acid substitutedpyrrolidine compounds, and their analogues thereof, which are GPR40 Gprotein-coupled receptor modulators, compositions containing them, andmethods of using them, for example, for the treatment of diabetes andrelated conditions.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a progressively debilitating disorder of epidemicproportions leading to various micro- and macrovascular complicationsand morbidity. The most common type of diabetes, type 2 diabetes, ischaracterized by increasing insulin resistance associated withinadequate insulin secretion after a period of compensatoryhyperinsulinemia. Free fatty acids (FFAs) are evidenced to influenceinsulin secretion from β cells primarily by enhancing glucose-stimulatedinsulin secretion (GSIS). G-protein coupled receptors (GPCRs) expressedin β cells are known to modulate the release of insulin in response tochanges in plasma glucose levels. GPR40, also known as fatty acidreceptor 1 (FFAR1), is a membrane-bound FFA receptor which ispreferentially expressed in the pancreatic islets and specifically in βcells and mediates medium to long chain fatty acid induced insulinsecretion. GPR40 is also expressed in enteroendocrine cells whereinactivation promotes the secretion of gut incretin hormones, such asGLP-1, GIP, CCK and PYY. To decrease medical burden of type 2 diabetesthrough enhanced glycemic control, GPR40 modulator compounds hold thepromise of exerting an incretin effect to promote GSIS as well aspotential combination with a broad range of antidiabetic drugs.

The present invention relates to novel substituted pyrrolidine compoundswhich have the ability to modulate GPR40. Such compounds are thereforepotentially useful for the treatment of diabetes and related conditions.

SUMMARY OF THE INVENTION

The present invention provides substituted pyrrolidine compounds, andtheir analogues thereof, which are useful as GPR40 modulators, includingstereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs,or solvates thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, polymorphs, or solvatesthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, polymorphs, or solvates thereof.

The present invention also provides a crystalline form of one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, polymorphs, or solvates thereof.

The compounds of the invention may be used in the treatment of multiplediseases or disorders associated with GPR40, such as diabetes andrelated conditions, microvascular complications associated withdiabetes, the macrovascular complications associated with diabetes,cardiovascular diseases, Metabolic Syndrome and its componentconditions, disorders of glucose metabolism, obesity and other maladies.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment of multiple diseases or disordersassociated with GPR40.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present disclosure provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof, wherein

X is independently selected from: a bond, O, S, NH, N(C₁₋₄ alkyl), CH₂,CH₂CH₂, CH(C₁₋₄ alkyl), OCH₂, CH₂O, OCH₂CH₂, and CH₂CH₂O;

ring A is independently

ring B is independently a 4- to 7-membered saturated heterocyclecontaining carbon atoms, the nitrogen atom shown in the ring B and 0-1additional heteroatom selected from N, O, and S; and ring B issubstituted with 0-4 R²;

R¹ is independently

phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containingcarbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S;wherein said phenyl, benzyl, naphthyl and heteroaryl are eachsubstituted with 0-3 R⁶;

R², at each occurrence, is independently selected from: ═O, OH, halogen,C₁₋₆ alkyl substituted with 0-1 R¹², C₁₋₆ alkoxy substituted with 0-1R¹², C₁₋₄ haloalkyl substituted with 0-1 R¹², C₁₋₄ haloalkoxysubstituted with 0-1 R¹², —(CH₂)_(m)—C₃₋₆ carbocycle substituted with0-1 R¹², and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbonatoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S); wherein saidheteroaryl is substituted with 0-1 R¹²;

when two R² groups are attached to two different carbon atoms, they maycombine to form a 1- to 3-membered carbon atom bridge over ring B;

when two R² groups are attached to the same carbon, they may combine,together with the carbon atom to which they are attached, to form a 3-to 6-membered carbon atom containing spiro ring;

R³ is independently selected from: C₁₋₆ alkyl substituted with R¹⁰, C₂₋₆alkenyl substituted with R¹⁰, C₂₋₆ alkynyl substituted with R¹⁰, C₁₋₄haloalkyl substituted with R¹⁰, —O(CH₂)₁₋₂O(CH₂)₁₋₄ R¹⁰, OR⁹, SR⁹,C(O)OR⁹, CO₂R⁹, S(O)R⁹, SO₂R⁹, and CONHR⁹;

R⁴ and R^(4a) are independently selected from: H, halogen, C₁₋₆ alkyl,C₁₋₆ alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle;

R⁵, at each occurrence, is independently selected from: halogen, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

R⁶, at each occurrence, is independently selected from: halogen, OH,C₁₋₄ alkylthio, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₁₋₈ alkyl substituted with 0-1 R⁷, C₁₋₆ alkoxysubstituted with 0-1 R⁷, —(O)_(n)—(CH₂)_(m)—(C₃₋₁₀ carbocyclesubstituted with 0-2 R⁷), and —(CH₂)_(m)-(5- to 10-membered heteroarylcontaining carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O,and S); wherein said heteroaryl is substituted with 0-2 R⁷;

R⁷, at each occurrence, is independently selected from: halogen, OH,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,SO₂(C₁₋₂ alkyl), and phenyl;

R⁸ is independently selected from: H and C₁₋₄ alkyl;

R⁹, at each occurrence, is independently selected from: C₁₋₆ alkylsubstituted with substituted with R¹⁰, and C₁₋₄ haloalkyl substitutedwith R¹⁰;

R¹⁰, at each occurrence, is independently selected from: CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), andtetrazolyl;

R¹¹, at each occurrence, is independently selected from: H, C₁₋₄ alkyland benzyl;

R¹², at each occurrence, is independently selected from: OH, halogen,CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₄alkyl), and tetrazolyl;

m, at each occurrence, is independently 0, 1, or 2; and

n, at each occurrence, is independently 0 or 1.

In a second aspect, the present disclosure provides a compound ofFormula (I), wherein R⁴ is hydrogen and R⁸ is hydrogen, furthercharacterized by Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof, wherein

X is independently selected from: O, N(CH₃), CH₂, CH₂O, and CH₂CH₂O;

ring A is independently

ring B is independently a 4- to 7-membered saturated heterocyclecontaining carbon atoms and the nitrogen atom shown in ring B; and ringB is substituted with 0-4 R²;

R¹ is independently

phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containingcarbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S;wherein said phenyl, benzyl, naphthyl and heteroaryl are eachsubstituted with 0-3 R⁶;

R², at each occurrence, is independently selected from: ═O, OH, halogen,C₁₋₄ alkyl substituted with 0-1 R¹², C₁₋₄ alkoxy substituted with 0-1R¹², C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and benzyl;

when two R² groups are attached to two different carbon atoms, they maycombine to form a 1- to 3-membered carbon atom bridge over ring B;

when two R² groups are attached to the same carbon, they may combine,together with the carbon atom to which they are attached, to form a 3-to 6-membered carbon atom containing spiro ring;

R³ is independently selected from: C₁₋₄ alkyl substituted with R¹⁰, C₁₋₄alkoxy substituted with R¹⁰, C₁₋₄ haloalkyl substituted with R¹⁰, C₁₋₄haloalkoxy substituted with R¹⁰, OR⁹, and —O(CH₂)₁₋₂O(CH₂)₁₋₄ R¹⁰;

R^(4a) is independently selected from: H, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle;

R⁵, at each occurrence, is independently selected from: halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy;

R⁶, at each occurrence, is independently selected from: halogen, OH,C₁₋₄ alkylthio, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₁₋₈ alkyl substituted with 0-1 R⁷, C₁₋₄ alkoxysubstituted with 0-1 R⁷, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ carbocycle substitutedwith 0-2 R⁷), —(CH₂)_(m)-(naphthyl substituted with 0-2 R⁷), and—(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4heteroatoms selected from N, O, and S; wherein said heteroaryl issubstituted with 0-2 R⁷);

R⁷, at each occurrence, is independently selected from: halogen, OH,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂,SO₂(C₁₋₂ alkyl), and phenyl;

R⁹, at each occurrence, is independently selected from: C₁₋₆ alkylsubstituted with substituted with R¹⁰, and C₁₋₄ haloalkyl substitutedwith R¹⁰;

R¹⁰, at each occurrence, is independently selected from: CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), andtetrazolyl;

R¹¹, at each occurrence, is independently selected from: H, C₁₋₄ alkyland benzyl;

R¹², at each occurrence, is independently selected from: halogen, CN,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₄alkyl), and tetrazolyl;

m, at each occurrence, is independently 0, 1, or 2; and

n, at each occurrence, is independently 0 or 1.

In a third aspect, the present disclosure includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a polymorph, or a solvate thereof, within the scope ofthe first or second aspect, wherein

ring A is independently

ring B is independently selected from:

R¹ is independently

phenyl substituted with 0-3 R⁶ or a heteroaryl substituted with 0-2 R⁶;wherein said heteroaryl is selected from: furanyl, oxazolyl, thiazolyl,pyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

R², at each occurrence, is independently selected from: OH, halogen,C₁₋₄ alkyl substituted with 0-1 R¹², C₁₋₄ alkoxy substituted with 0-1R¹², and benzyl;

R³ is independently selected from: C₁₋₄ alkyl substituted with 1 R¹⁰,C₁₋₄ alkoxy substituted with 1 R¹⁰, C₁₋₄ haloalkyl substituted with 1R¹⁰, OR⁹ and C₁₋₄ haloalkoxy substituted with 1 R¹⁰;

R^(4a) is independently selected from: H, halogen C₁₋₄ alkyl, C₁₋₄alkoxy, and C₃₋₆ cycloalkyl;

R⁶, at each occurrence, is independently selected from: halogen, OH,C₁₋₆ alkyl substituted with 0-1 OH, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₃₋₆cycloalkyl substituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenylsubstituted with 0-2 C₁₋₄ alkyl, —O—C₃₋₆ cycloalkyl, benzyl, andoxazolyl;

R⁹, at each occurrence, is independently selected from: C₁₋₆ alkylsubstituted with substituted with R¹⁰, and C₁₋₄ haloalkyl substitutedwith R¹⁰;

R¹⁰, at each occurrence, is independently selected from: CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), andtetrazolyl; and

R¹², at each occurrence, is independently selected from: halogen, CN,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₂alkyl), and tetrazolyl.

In a fourth aspect, the present invention includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a polymorph, or a solvate thereof, within the scope ofthe first, second or third aspect, wherein

R¹ is independently

phenyl substituted with 0-3 R⁶, or a heteroaryl substituted with 0-2 R⁶;wherein said heteroaryl is selected from: thiazolyl, pyridinyl,pyrimidinyl, pyrazinyl,

In a fifth aspect, the present disclosure includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a polymorph, or a solvate thereof, within the scope ofany of the above aspect, wherein

ring B is independently selected from:

R¹ is independently phenyl substituted with 0-3 R⁶, pyridinylsubstituted with 0-2 R⁶, pyrazinyl substituted with 0-2 R⁶, pyrimidinylsubstituted with 0-2 R⁶, thiazolyl substituted with 0-2 R⁶,

and

R², at each occurrence, is independently selected from: OH, halogen,C₁₋₄ alkyl substituted with 0-1 CN, C₁₋₄ alkoxy, benzyl, andtetrazolylmethyl.

In a sixth aspect, the present disclosure includes a compound of Formula(I) or (II), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a polymorph, or a solvate thereof, within the scope ofany of the above aspect, wherein

ring B is independently selected from:

R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶or pyridinyl substituted with 0-2 R⁶;

R², at each occurrence, is independently selected from: halogen, C₁₋₄alkyl, C₁₋₄ alkoxy and tetrazolylmethyl;

R³, at each occurrence, is independently selected from: C₁₋₄ alkylsubstituted with R¹⁰, C₁₋₄ alkoxy substituted with R¹⁰, OR⁹ and—O(CH₂)₁₋₂O(CH₂)₁₋₄ R¹⁰; and

R⁶, at each occurrence, is independently selected from: halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkylsubstituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2C₁₋₄ alkyl, and benzyl;

R⁹, at each occurrence, is independently selected from: C₁₋₆ alkylsubstituted with substituted with R¹⁰, and C₁₋₄ haloalkyl substitutedwith R¹⁰; and

R¹⁰, at each occurrence, is independently selected from: CN, C₁₋₄alkoxy, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), andtetrazolyl.

In a seventh aspect, the present disclosure includes a compound ofFormula (III), (IIIa), (IIIb) or (IIIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof, wherein

R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶or pyridinyl substituted with 0-2 R⁶;

R², at each occurrence, is independently selected from: halogen, C₁₋₄alkyl, and C₁₋₄ alkoxy;

R³, at each occurrence, is independently selected from: C₁₋₄ alkylsubstituted with C₁₋₄ alkoxy, and C₁₋₄ alkoxy substituted with C₁₋₄alkoxy;

R^(4a), at each occurrence, is independently selected from: H, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, and cyclopropyl;

R⁵, at each occurrence, is independently selected from: halogen, C₁₋₄haloalkyl, and C₁₋₆ alkoxy; and

R⁶, at each occurrence, is independently selected from: halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, andC₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl.

In an eighth aspect, the present disclosure includes a compound ofFormula (I) (II), (III), (IIIa), (IIIb) or (IIIc), or a stereoisomer, atautomer, a pharmaceutically acceptable salt, a polymorph, or a solvatethereof, within the scope of any of the above aspect, wherein

R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶or pyridinyl substituted with 0-2 R⁶;

R², at each occurrence, is independently selected from: halogen and C₁₋₂alkyl;

R³, at each occurrence, is independently selected from: C₁₋₄ alkylsubstituted with C₁₋₄ alkoxy, and C₁₋₄ alkoxy substituted with C₁₋₄alkoxy;

R^(4a), at each occurrence, is independently selected from: H andmethyl;

R⁵, at each occurrence, is independently selected from: halogen, C₁₋₄haloalkyl, and C₁₋₆ alkoxy; and

R⁶, at each occurrence, is independently selected from: halogen, C₁₋₆alkyl, and C₁₋₄ alkoxy.

In a ninth aspect, the present disclosure includes a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, a polymorph, or a solvate thereof.

In another aspect, the present disclosure includes a compound selectedfrom any subset list of compounds or a single compound from theexemplified examples within the scope of any of the above aspects.

In another embodiment, the compounds of the present invention havehGPR40 EC₅₀ values ≤5 μM.

In another embodiment, the compounds of the present invention havehGPR40 EC₅₀ values ≤1 μM.

In another embodiment, the compounds of the present invention havehGPR40 EC₅₀ values ≤0.5 μM.

In another embodiment, the compounds of the present invention havehGPR40 EC₅₀ values ≤0.2 μM.

In another embodiment, the compounds of the present invention havehGPR40 EC₅₀ values ≤0.1 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, a polymorph, or a solvatethereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, a polymorph, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, a polymorph, or a solvatethereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, a polymorph, or a solvatethereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). Examplesof additional therapeutic agent(s), according to the present inventioninclude, but are not limited to, anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents,anti-pancreatic agents, lipid lowering agents, anorectic agents, andappetite suppressants.

In a preferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agents are, for example,a DPP4 inhibitor (for example a member selected from saxagliptin,sitagliptin, vildagliptin, linagliptin, and alogliptin).

In a preferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agents are, for example,an SGLT2 inhibitor (for example a member selected from dapagliflozin,canagliflozin, empagliflozin and remagliflozin).

In another embodiment, the present invention provides a method for thetreatment of multiple diseases or disorders associated with GPR40,comprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

Examples of diseases or disorders associated with the activity of theGPR40 that can be prevented, modulated, or treated according to thepresent invention include, but are not limited to, diabetes,hyperglycemia, impaired glucose tolerance, gestational diabetes, insulinresistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy,diabetic kidney disease, acute kidney injury, cardiorenal syndrome,acute coronary syndrome, delayed wound healing, atherosclerosis and itssequelae, abnormal heart function, congestive heart failure, myocardialischemia, stroke, Metabolic Syndrome, hypertension, obesity, fatty liverdisease, dislipidemia, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein(HDL), high low-density lipoprotein (LDL), non-cardiac ischemia,pancreatitis, lipid disorders, and liver diseases such as NASH(Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty LiverDisease), liver cirrhosis, inflammatory bowel diseases incorporatingulcerative colitis and Crohn's disease, celiac disease, osteoarthritis,nephritis, psoriasis, atopic dermatitis, and skin inflammation.

In another embodiment, the present invention provides a method for thetreatment of diabetes, hyperglycemia, gestational diabetes, obesity,dyslipidemia, hypertension and cognitive impairment, comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method for thetreatment of diabetes, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of at least one of thecompounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of hyperglycemia, comprising administering to a patient inneed of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of obesity, comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of at least one of thecompounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of dyslipidemia, comprising administering to a patient in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of hypertension, comprising administering to a patient in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment of cognitive impairment, comprising administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment of multiplediseases or disorders associated with GPR40.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment of multiple diseases or disorders associated withGPR40.

In another embodiment, the present invention provides a method for thetreatment of multiple diseases or disorders associated with GPR40,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a first and second therapeutic agent, wherein thefirst therapeutic agent is a compound of the present invention.Preferably, the second therapeutic agent, for example, a DPP4 inhibitor(for example a member selected from saxagliptin, sitagliptin,vildagliptin, linagliptin and alogliptin).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment of multiple diseases or disorders associated with GPR40.

Where desired, the compound of the present invention may be used incombination with one or more other types of antidiabetic agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of antidiabetic agent that may be optionallyemployed in combination with the GPR40 receptor modulator of the presentinvention may be one, two, three or more antidiabetic agents orantihyperglycemic agents which may be administered orally in the samedosage form, in a separate oral dosage form, or by injection to producean additional pharmacological benefit.

The antidiabetic agents used in the combination with the GPR40 receptormodulator of the present invention include, but are not limited to,insulin secretagogues or insulin sensitizers, other GPR40 receptormodulators, or other antidiabetic agents. These agents include, but arenot limited to, DPP4 inhibitors (for example, sitagliptin, saxagliptin,alogliptin, linagliptin and vildagliptin), biguanides (for example,metformin and phenformin), sulfonyl ureas (for example, glyburide,glimepiride and glipizide), glucosidase inhibitors (for example,acarbose, miglitol), PPARγ agonists such as thiazolidinediones (forexample, rosiglitazone and pioglitazone), PPAR α/γ dual agonists (forexample, muraglitazar, tesaglitazar and aleglitazar), glucokinaseactivators, GPR119 receptor modulators (for example, MBX-2952, PSN821,and APD597), GPR120 receptor modulators (for example, as described inShimpukade, B. et al., J. Med. Chem., 55(9):4511-4515 (2012)), SGLT2inhibitors (for example, dapagliflozin, canagliflozin, empagliflozin andremagliflozin), MGAT inhibitors (for example, as described in Barlind,J. G. et al., Bioorg. Med. Chem. Lett., 23(9):2721-2726 (2013)), amylinanalogs such as pramlintide, and/or insulin.

The GPR40 receptor modulator of the present invention may also beoptionally employed in combination with agents for treating complicationof diabetes. These agents include PKC inhibitors and/or AGE inhibitors.

The GPR40 receptor modulator of the present invention may also beoptionally employed in combination with one or more hypophagic and/orweight-loss agents such as diethylpropion, phendimetrazine, phentermine,orlistat, sibutramine, lorcaserin, pramlintide, topiramate, MCHR1receptor antagonists, oxyntomodulin, naltrexone, Amylin peptide, NPY Y5receptor modulators, NPY Y2 receptor modulators, NPY Y4 receptormodulators, cetilistat, 5HT2c receptor modulators, and the like. TheGPR40 receptor modulator of the present invention may also be employedin combination with an agonist of the glucagon-like peptide-1 receptor(GLP-1 R), such as exenatide, liraglutide, GLP-1(1-36) amide,GLP-1(7-36) amide, GLP-1(7-37), which may be administered via injection,intranasal, or by transdermal or buccal devices.

Additional embodiments provide compounds having the structures:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

Another embodiment of the present invention includes the compound havingthe structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, apolymorph, or a solvate thereof.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsounderstood that each individual element of the embodiments is its ownindependent embodiment.

Furthermore, any element of an embodiment is meant to be combined withany and all other elements from any embodiment to describe an additionalembodiment.

III. Chemistry

Throughout the specification, examples and the appended claims, a givenchemical formula or name shall encompass all stereo and optical isomersand racemates thereof where such isomers exist. The term“stereoisomer(s)” refers to compound(s) which have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Unless otherwise indicated, all chiral (enantiomericand diastereomeric) and racemic forms are within the scope of theinvention. The term “chiral” refers to molecules which have the propertyof non-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. The terms “racemic mixture” and “racemate” refer to anequimolar mixture of two enantiomeric species, devoid of opticalactivity.

Many geometric isomers of C═C double bonds, C═N double bonds, ringsystems, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis- andtrans- (or E- and Z-) geometric isomers of the compounds of the presentinvention are described and may be isolated as a mixture of isomers oras separated isomeric forms.

The present compounds can be isolated in optically active or racemicforms. Optically active forms may be prepared by resolution of racemicforms or by synthesis from optically active starting materials. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. When enantiomeric or diastereomeric products are prepared,they may be separated by conventional methods, for example, bychromatography or fractional crystallization.

Depending on the process conditions the end products of the presentinvention are obtained either in free (neutral) or salt form. Both thefree form and the salts of these end products are within the scope ofthe invention. If so desired, one form of a compound may be convertedinto another form. A free base or acid may be converted into a salt; asalt may be converted into the free compound or another salt; a mixtureof isomeric compounds of the present invention may be separated into theindividual isomers. Compounds of the present invention, free form andsalts thereof, may exist in multiple tautomeric forms, in which hydrogenatoms are transposed to other parts of the molecules and the chemicalbonds between the atoms of the molecules are consequently rearranged. Itshould be understood that all tautomeric forms, insofar as they mayexist, are included within the invention.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₆alkyl” or “C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkylgroup can be unsubstituted or substituted with at least one hydrogenbeing replaced by another chemical group. Example alkyl groups include,but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyland isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl(e.g., n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene”is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and butoxy (e.g., n-butoxy, isobutoxy andt-butoxy). Similarly, “alkylthio” or “thioalkoxy” represents an alkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”. Theterm “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenylis intended to include C₄, C₅, and C₆ cycloalkenyl groups. Examplecycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl”. A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Lewis, R. J., ed., Hawley'sCondensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc.,New York (1997). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl,imidazopyridazinyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, pyrimidinyl, pyrazinyl, imidazolyl,imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl,1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl,benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl,benzthiazolyl, benzisothiazolyl, imidazolopyridinyl, imidazopyridazinyl,isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl andpyrazolopyrimidinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, pyrimidinyl, imidazolyl, imidazolidinyl,indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+), calcium(Ca²⁺)ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, Fourth Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (1) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Compounds of the present invention can form salts which are also withinthe scope of this invention. Unless otherwise indicated, reference to aninventive compound is understood to include reference to one or moresalts thereof. Pharmaceutically acceptable salts are preferred. However,other salts may be useful, e.g., in isolation or purification stepswhich may be employed during preparation, and thus, are contemplatedwithin the scope of the invention.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, L. V., Jr.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of Formula (I)) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985);

b) Widder, K. et al., eds., Methods in Enzymology, 112:309-396, AcademicPress (1985);

c) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”, ATextbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen,P. et al., eds., Harwood Academic Publishers, publ. (1991);

d) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

e) Nielsen, N. M. et al., J. Pharm. Sci., 77:285 (1988);

f) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

g) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods andPrinciples in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield Formula (I) compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (Second Edition,reproduced (2006)); Testa, B. et al., Hydrolysis in Drug and ProdrugMetabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH,Zurich, Switzerland (2003); Wermuth, C. G., ed., The Practice ofMedicinal Chemistry, Third Edition, Academic Press, San Diego, Calif.(2008).

The present invention also includes isotopically-labeled compounds ofthe invention, wherein one or more atoms is replaced by an atom havingthe same atomic number, but an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes suitable for inclusion in the compounds of the inventioninclude isotopes of hydrogen, such as ²H (also represented as ‘D’ fordeuterium) and ³H, carbon such as ¹¹C, ¹³C, and ¹⁴C, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O, and ¹⁸O. Certainisotopically-labeled compounds of the invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, ³H, andcarbon-14, ¹⁴C, are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection. Substitutionwith heavier isotopes such as deuterium, ²H, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increase in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁵O, and ¹³N, can be useful in PositronEmission Topography (PET) studies for examining substrate receptoroccupancy. Isotopically-labeled compounds of the invention can generallybe prepared by conventional techniques known to those skilled in the artor by processes analogous to those described herein, using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

As used herein, “polymorph(s)” refer to crystalline form(s) having thesame chemical structure/composition but different spatial arrangementsof the molecules and/or ions forming the crystals. Compounds of thepresent invention can be provided as amorphous solids or crystallinesolids. Lyophilization can be employed to provide the compounds of thepresent invention as a solid.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “A” for “Angstroms”, “° C.” for degreesCelsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg”for milligram or milligrams, “L” for liter or liters, “mL or ml” formilliliter or milliliters, “L” for microliter or microliters, “N” fornormal, “M” for molar, “N” for normal, “mmol” for millimole ormillimoles, “min” for minute or min, “h” for hour or h, “rt” for roomtemperature, “RT” for retention time, “atm” for atmosphere, “psi” forpounds per square inch, “conc.” for concentrate, “aq” for “aqueous”,“sat” or “sat'd” for saturated, “MW” for molecular weight, “mp” formelting point, “MS” or “Mass Spec” for mass spectrometry, “ESI” forelectrospray ionization mass spectroscopy, “HR” for high resolution,“HRMS” for high resolution mass spectrometry, “LCMS” for liquidchromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “RP-Prep. HPLC” forreverse phase preparative HPLC, “TLC” or “tlc” for thin layerchromatography, “NMR” for nuclear magnetic resonance spectroscopy, “nOe”for nuclear Overhauser effect spectroscopy, “¹H” for proton, “δ” fordelta, “s” for singlet, “d” for doublet, “t” for triplet, “q” forquartet, “m” for multiplet, “br” for broad, “Hz” for hertz, and “α”,“β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar toone skilled in the art.

-   AcCl acetyl chloride-   Ac₂O acetic anhydride-   AcOH acetic acid-   ADDP 1,1′-(azodicarbonyl)dipiperidine-   Ag₂O silver oxide-   AlMe₃ trimethylaluminum-   atm atmosphere-   9-BBN 9-borabicyclo[3.3.1]nonane-   BF₃.OEt₂ boron trifluoride diethyl etherate-   BF₃.SMe₂ boron trifluoride dimethyl sulfide-   BH₃.DMS borane dimethyl sulfide complex-   Bn benzyl-   Boc tert-butyloxycarbonyl-   Boc₂O di-tert-butyl dicarbonate-   Bu butyl-   Bu₂BOTf dibutylboron trifluoromethanesulfonate-   n-BuOH n-butanol-   Bu₃P tributylphosphine-   CBr₄ carbon tetrachloride-   CDCl₃ deutero-chloroform-   CD₂Cl₂ deutero-dichloromethane-   cDNA complimentary DNA-   CH₂Cl₂ or DCM dichloromethane-   CH₃CN or MeCN acetonitrile-   CHCl₃ chloroform-   CO₂ carbon dioxide-   CSA camphorsulfonic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper(II) acetate-   CuI copper(I) iodide-   CuBr.SMe₂ copper(I) bromide dimethylsulfide complex-   DAST (diethylamino)sulfur trifluoride-   DBAD di-tert-butyl azodicarboxylate-   DEAD diethyl azodicarboxylate-   DIAD diisopropyl azodicarboxylate-   DIBAL-H diisobutylaluminum hydride-   DIPEA diisopropylethylamine-   DMAP 4-(dimethylamino)pyridine-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   DtBPF 1,1′-bis(di-tert-butylphosphino)ferrocene-   EDTA ethylenediaminetetraacetic acid-   Et ethyl-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOCOCl ethyl chloroformate-   EtOH ethanol-   H₂ molecular Hydrogen-   H₂O₂ hydrogen peroxide-   H₂SO₄ sulfuric acid-   HCl hydrochloric acid-   Hex hexanes-   i-Bu isobutyl-   i-Pr isopropyl-   i-PrOH or IPA isopropanol-   KCN potassium cyanide-   K₂CO₃ potassium carbonate-   K₂HPO₄ dipotassium phosphate-   KHSO₄ potassium bisulfate-   KI potassium iodide-   KOH potassium hydroxide-   KOtBu potassium tert-butoxide-   K₃PO₄ tripotassium phosphate-   LAH lithium aluminum hydride-   LDA lithium diisopropylamide-   L.G. leaving group-   LHMDS lithium hexamethyldisilazide-   LiBH₄ lithium borohydride-   LiOH lithium hydroxide-   L-Selectride lithium tri-sec-butylborohydride-   Me methyl-   MeI iodomethane-   MeLi methyl lithium-   MeOH methanol-   MgSO₄ magnesium sulfate-   MSA methanesulfonic acid-   MsCl methanesulfonyl chloride-   MTBE methyl tert-butylether-   NaBH(OAc)₃ sodium triacetoxyborohydride-   NaDCC sodium dichloroisocyanurate-   NaHMDS sodium hexamethyldisilazide-   NaNO₂ sodium nitrite-   Na₂SO₄ sodium sulfate-   Na₂S₂O₃ sodium thiosulfate-   NaBH₄ sodium borohydride-   NaCl sodium chloride-   NaCN sodium cyanide-   NCS N-chlorosuccinimide-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   NaOtBu sodium tert-butoxide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   Pd(OAc)₂ palladium(II) acetate-   Pd(OH)₂ palladium hydroxide-   Pd/C palladium on carbon-   PdCl₂(dppf)    1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-   PdCl₂(dtbpf) [1,1′-bis(di-tert-butylphosphino)ferrocene]    dichloropalladium(II)-   PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II) dichloride-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(Ph₃P)₄ tetrakis(triphenylphosphine)palladium(0)-   P.G. protecting group-   Ph phenyl-   Ph₃P triphenylphosphine-   Pr propyl-   PS polystyrene-   PtO₂ platinum(IV) oxide-   SFC supercritical fluid chromatography-   SiO₂ silica oxide-   SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl-   SPhos precatalyst    chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)    [2-(2-aminoethylphenyl)]palladium(II)—methyl-t-butyl ether adduct-   TBAF tetrabutylammonium fluoride-   t-Bu tert-butyl-   TBDPS-Cl tert-butylchlorodiphenylsilane-   TBS-Cl tert-butyldimethylsilyl chloride-   TBSOTf tert-butyldimethylsilyl trifluoromethanesulfonate-   TCCA trichloroisocyanuric acid-   TEA or NEt₃ triethylamine-   TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy-   TFA trifluoroacetic acid-   Tf₂O trifluoromethanesulfonic anhydride-   THF tetrahydrofuran-   TiCl₄ titanium tetrachloride-   TMS-Cl chlorotrimethylsilane-   TsCl 4-methylbenzene-1-sulfonyl chloride-   TsOH orpTsOH para-toluenesulfonic acid-   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P. G. M. et al., Protecting Groups inOrganic Synthesis, Fourth Edition, Wiley (2007)). General methods oforganic synthesis and functional group transformations are found in:Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, N.Y. (1991); Smith, M. B. et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure. Sixth Edition, Wiley &Sons, New York, N.Y. (2007); Katritzky, A. R. et al., eds.,Comprehensive Organic Functional Groups Transformations II, SecondEdition, Elsevier Science Inc., Tarrytown, N.Y. (2004); Larock, R. C.,Comprehensive Organic Transformations, VCH Publishers, Inc., New York,N.Y. (1999), and references therein.

Methods for synthesis of a large variety of substituted pyrrolidinecompounds useful as starting materials for the preparation of compoundsof the present invention are well known in the art. For examples ofmethods useful for the preparation of pyrrolidine materials see thefollowing references and citations therein: Katritzky et al., eds.,Comprehensive Heterocyclic Chemistry, Pergamon Press Inc., New York(1996); Bellina, F. et al., Tetrahedron, 62:7213 (2006); Wolfe, J. P.,Eur. J. Org. Chem., 571 (2007); Deng, Q.-H. et al., Organic Letters,10:1529 (2008); Pisaneschi, F. et al., Synlett, 18:2882 (2007); Najera,C. et al., Angewandte Chemie, InternationalEdition, 44(39):6272 (2005);Sasaki, N. A., Methods in Molecular Medicine, 23(PeptidomimeticsProtocols):489 (1999); Zhou, J.-Q. et al., Journal of Organic Chemistry,57(12):3328 (1992); Coldham, I. et al., Tetrahedron Letters, 38(43):7621(1997); Schlummer, B. et al., Organic Letters, 4(9):1471 (2002); Larock,R. C. et al., Journal of Organic Chemistry, 59(15):4172 (1994);Galliford, C. V. et al., Organic Letters, 5(19):3487 (2003); Kimura, M.et al., Angewandte Chemie, International Edition, 47(31):5803 (2008);Ney, J. E. et al., Adv. Synth. Catal., 347:1614 (2005); Paderes, M. C.et al., Organic Letters, 11(9):1915 (2009); Wang, Y.-G. et al., OrganicLetters, 11(9):2027 (2009); Cordero, F. M. et al., Journal of OrganicChemistry, 74(11):4225 (2009); Hoang, C. T. et al., Journal of OrganicChemistry, 74(11):4177 (2009). Luly, J. R. et al., Journal of theAmerican Chemical Society, 105:2859 (1983); Kimball, F. S. et al.,Bioorganic and Medicinal Chemistry, 16:4367 (2008); Bertrand, M. B. etal., Journal of Organic Chemistry, 73(22):8851 (2008); Browning, R. G.et al., Tetrahedron, 60:359 (2004); Ray, J. K. et al., Bioorganic andMedicinal Chemistry, 2(12): 1417 (1994); Evans, G. L. et al., Journal ofthe American Chemical Society, 72:2727 (1950); Stephens, B. E. et al.,Journal of Organic Chemistry, 74(1):254 (2009); Spangenberg, T. et al.,Organic Letters, 11(2):261 (2008); and Qiu, X.-L. et al., Journal ofOrganic Chemistry, 67(20):7162 (2008).

Compounds of Formula (I) may be synthesized starting with pyrrolidines Avia coupling to intermediate B using, for example, CuI and NaOH to giveprolinol C, as depicted in Scheme 1. Activation of intermediate C, viamethanesulfonyl chloride and base, for example, and displacement withsodium cyanide leads to nitrile D. Removal of P.G. on intermediate D,such as hydrogenolysis (when P.G. is a benzyl ether), gives phenol E. R¹group of intermediate J is appended via displacement of L.G. inintermediate F via amine H using S-Phos precatalyst and base, such asLiHMDS or, optionally via uncatalyzed displacement of L.G. The hydroxylof amine J can be activated with, for example, para-toluenesulfonylchloride and base, such as pyridine, to give tosylate K. Intermediate Kand phenol E can be coupled using a base, such as Cs₂CO₃, to giveintermediate L. The cyano or methyl ester group can be hydrolyzed viaNaOH, for example, to provide compounds of Formula (I).

Compounds of Formula (I) can be synthesized by reaction of alcohol Jwith phenol E via a Mitsunobu reaction using an azodicarboxylate, suchas ADDP, and a phosphine (e.g., Bu₃P) as demonstrated in Scheme 2 togive compound L. The intermediate L can be converted to compounds ofFormula (I) by hydrolysis with base, such as NaOH.

Compounds of Formula (I) may be synthesized beginning with ketone CC,which can be reduced to alcohol H by a hydride source or dynamic kineticresolution using glucose dehydrogenase, for example, followed bydeprotection of the P.G. by hydrogenolysis (when P.G. is a benzyl group)as shown in Scheme 2.2. Displacement of a L.G., such as a chloride, oncompound F using a base, such as K₂CO₃, provides compound J. Thehydroxyl of compound J can displace a L.G. on intermediate DD using abase, such as KOtBu, to give compound EE. The nitro group can be reducedvia Fe and NH₄Cl, for example, to give amine FF.

Acylated chiral auxiliary HH can be reacted with2,2-dimethoxyacetaldehyde GG using a Lewis acid, such as TiCl₄ orBu₂BOTf along with a base, such as DIPEA, to give aldol product JJ. Thechiral auxiliary is removed using AlMe₃ and N,O-dimethylhydroxylaminehydrochloride to provide Weinreb amide KK. Intermediate KK can bealkylated with intermediate LL using a base, such as NaH, and a phasetransfer reagent, such as TBAF, to give intermediate MM. The Weinrebamide MM can be reacted with a hydride reagent, such as DIBAL-H, to givealdehyde NN. Intermediate NN can undergo reaction with CBr₄ and Ph₃P togive dibromide 00. The dibromide 00 can be reacted with a base, such asn-BuLi, and an acylating reagent, such as ethyl chloroformate, to givealkyne PP. The alkyne can be hydrogenated using a Pd catalyst, such asLindlar catalyst, to give alkene QQ. The acetal group of intermediate QQcan be removed using aqueous acid, such as HCl, to give aldehyde RR.This aldehyde can undergo reductive amination with amine FF using ahydride source, such as NaBH(OAc)₃, to provide amine SS. Amine SS canundergo cyclization to intermediate L using a base, such as NaOtBu.Hydrolysis of ester L via LiOH, for example, can provide compounds ofFormula (I).

Alternatively, compounds of Formula (I) may be synthesized starting withethyl 1-benzyl-4-oxopiperidine-3-carboxylate (intermediate M), which canbe reacted with R²-L.G., as an intermediate N, using a base, such asKOtBu, to provide β-ketoester O as depicted in Scheme 3. The ester canbe removed via decarboxylation with acid, e.g., HCl, to providepiperidinone P. The methyl iodonium salt Q can be formed frompiperidinone P using MeI. The salt Q can be converted to thepiperidinone S by reaction with an amine R and base (e.g., K₂CO₃). Theketone S can be reduced using a hydride source, such as NaBH₄, to givealcohol J. Alcohol J can be converted to compounds of Formula (I)according to the sequence depicted in Scheme 1 or Scheme 2.

Compounds of Formula (IIIa) may be synthesized via reaction ofpyrrolidine T with NaDCC followed by elimination using a base (e.g.,NEt₃) as depicted in Scheme 4. The resultant intermediate U can beprotected with a protecting group and base (e.g., 2,6-lutidine) to giveV. A Michael reaction with a Grignard or alkyl lithium reagent W andCuBr.SMe₂ gives intermediate X. Deprotection of intermediate X revealshydroxyl Y, which can be alkylated with an alkoxyalkyl group Z and base,such as NaH to give AA. The ester can be reduced with a hydride source,such as LiBH₄, and then the protecting group on the nitrogen can beremoved. The resultant intermediate BB can be converted to Formula(IIIa) via an analogous sequence to those shown in Schemes 1 or 2.

IV. Biology

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. It is diagnosed as a group of disorders characterizedby abnormal glucose homeostasis resulting in elevated blood glucose.Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic abnormality is generallycharacterized by hyperglycemia and alterations in carbohydrate, fat andprotein metabolism caused by absent or reduced insulin secretion and/orineffective insulin secretion. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of diabetic syndrome. Strikingly, diabetesis the fourth leading cause of global death by disease, the largestcause of kidney failure in developed countries, the leading cause ofvision loss in industrialized countries and has the greatest prevalenceincrease in developing countries.

Type 2 diabetes, which accounts for 90% of diabetes cases, ischaracterized by increasing insulin resistance associated withinadequate insulin secretion after a period of compensatoryhyperinsulinemia. The reasons for 3 cell secondary failure are notcompletely understood. Acquired pancreatic islet damage or exhaustionand/or genetic factors causing susceptibility to islet secretoryinsufficiency have been hypothesized.

Free fatty acids (FFAs) are evidenced to influence insulin secretionfrom β cells primarily by enhancing glucose-stimulated insulin secretion(GSIS). Although glucose is recognized as the major stimulator ofinsulin secretion from 1 cells, other stimuli, such as amino acids,hormones, and FFAs, also regulate insulin secretion. Thus, under normalsettings, insulin secretion from β cells in response to food intake isevoked by the collective stimuli of nutrients, such as glucose, aminoacids, and FFAs, and hormones like the incretin glucagon-like peptide 1(GLP-1). Fatty acids are also known to stimulate the secretion ofseveral gut satiety hormones, including cholocystokinine (CCK), GLP-1,and peptide YY (PYY).

G-protein coupled receptors (GPCRs) expressed in β cells are known tomodulate the release of insulin in response to changes in plasma glucoselevels. GPR40, also known as fatty acid receptor 1 (FFAR1), is amembrane-bound FFA receptor which is preferentially expressed in thepancreatic islets and specifically in β cells. GPR40 (e.g., human GPR40,RefSeq mRNA ID NM_005303; e.g., mouse GPR40 RefSeq mRNA ID NM_194057) isa GPCR located at chromosome 19q13.12. GPR40 is activated by medium tolong chain fatty acids and thereby triggering a signaling cascade thatresults in increased levels of [Ca²⁺]_(i) in β cells and subsequentstimulation of insulin secretion (Itoh et al., Nature, 422:173-176(2003)). Selective small molecule agonists of GPR40 have been shown topromote GSIS and reduce blood glucose in mice (Tan et al., Diabetes,57:2211-2219 (2008)). Briefly, when activators of GPR40 are administeredto either normal mice or mice that are prone to diabetes due to geneticmutation, prior to a glucose tolerance test, improvements in glucosetolerance are observed. A short-lived increase in plasma insulin levelsare also observed in these treated mice. It has also been shown thatGPR40 agonists restore GSIS in pancreatic β-cells from the neonatal STZrats suggesting that GPR40 agonists will be efficacious in diabeticswith compromised β-cell function and mass. Fatty acids are known tostimulate the secretion of several gut satiety hormones, includingcholocystokinine (CCK), GLP-1, and peptide YY (PYY), and GPR40 has beenshown to colocalize with cells that secrete such hormones (Edfalk etal., Diabetes, 57:2280-2287 (2008); Luo et al., PLoS ONE, 7:1-12(2012)). Fatty acids are also known to play a role in neuronaldevelopment and function, and GPR40 has been reported as a potentialmodulator of the fatty acid effects on neurons (Yamashima, T., Progressin Neurobiology, 84:105-115 (2008)).

Given the increase in the worldwide patient population afflicted by type2 diabetes, there is a need for novel therapies which are effective withminimal adverse events. To decrease medical burden of type 2 diabetesthrough enhanced glycemic control, GPR40 modulator compounds of thepresent invention are being investigated here for their incretin effectto promote GSIS as well as the potential combination with a broad rangeof anti-diabetic drugs.

The term “modulator” refers to a chemical compound with capacity toeither enhance (e.g., “agonist” activity) or partially enhance (e.g.,“partial agonist” activity) or inhibit (e.g., “antagonist” activity or“inverse agonist” activity) a functional property of biological activityor process (e.g., enzyme activity or receptor binding); such enhancementor inhibition may be contingent on the occurrence of a specific event,such as activation of a signal transduction pathway, receptorinternalization, and/or may be manifest only in particular cell types.

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known anti-diabetic agents,in one or more of the following categories that are given as examples,and are not intended to be limiting: (a) pharmacokinetic properties,including oral bioavailability, half life, and clearance; (b)pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor;(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index with less propensity for hypoglycemia.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with a GPR40modulator. Exemplary subjects include human beings of any age with riskfactors for metabolic disease. Common risk factors include, but are notlimited to, age, sex, weight, family history, or signs of insulinresistance such as acanthosis nigricans, hypertension, dislipidemia, orpolycystic ovary syndrome (PCOS).

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; (b)relieving the disease-state, i.e., causing regression of the diseasestate; and/or (c) preventing the disease-state from occurring in amammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it.

As used herein, “preventing” or “prevention” cover the preventivetreatment (i.e., prophylaxis and/or risk reduction) of a subclinicaldisease-state in a mammal, particularly in a human, aimed at reducingthe probability of the occurrence of a clinical disease-state. Patientsare selected for preventative therapy based on factors that are known toincrease risk of suffering a clinical disease state compared to thegeneral population. “Prophylaxis” therapies can be divided into (a)primary prevention and (b) secondary prevention. Primary prevention isdefined as treatment in a subject that has not yet presented with aclinical disease state, whereas secondary prevention is defined aspreventing a second occurrence of the same or similar clinical diseasestate.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to modulate GPR40 and/or to prevent or treat thedisorders listed herein. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thepreventive or therapeutic effect, whether administered in combination,serially, or simultaneously.

In Vitro GPR40 Assays

FDSS-Based Intracellular Calcium Assay

Cell lines expressing GPR40 are generated using the pDEST-3×FLAG geneexpression system and are cultured in culture medium comprising thefollowing components: F12 (Gibco #11765), 10% lipid deprived fetalbovine serum, 250 μg/ml zeocin and 500 μg/ml G418. To conduct thefluorescent imaging plate reader (FLIPR)-based calcium flux assay tomeasure intracellular Ca²⁺ response, cells expressing GPR40 are platedon 384 well plates (BD Biocoat #356697) at a density of 20,000 cells/20μL medium per well in phenol red and serum-free DMEM (Gibco #21063-029)and incubated overnight. Using BD kit #s 80500-310 or -301, the cellsare incubated with 20 μL per well of Hank's buffered salt solution with1.7 mM probenecid and Fluo-3 at 37° C. for 30 min. Compounds aredissolved in DMSO and diluted to desired concentrations with assaybuffer and added to the cells as 3× solution (20 μL per well). Runfluorescence/luminescence reader FDSS (Hamamatsu) to read intracellularCa²⁺ response.

The exemplified Examples disclosed below were tested in the Human GRP40In Vitro assay described above and found having hGRP40 modulatingactivity.

GPR40 IP-One HTRF Assays in HEK293/GPR40 Inducible Cell Lines

Human, mouse and rat GPR40-mediated intracellular IP-One HTRF assayswere established using human embryonic kidney HEK293 cells stablytransfected with a tetracycline-inducible human, mouse or rat GPR40receptor. Cells were routinely cultured in growth medium containing DMEM(Gibco Cat. #12430-047), 10% qualified FBS (Sigma, Cat. #F2442), 200μg/mL hygromycin (Invitrogen, Cat. #16087-010) and 1.5 μg/mL blasticidin(Invitrogen, Cat. #R210-01). About 12-15 million cells were passed intoa T175 tissue culture flask (BD Falcon 353112) with growth medium andincubated for 16-18 hours (overnight) at 37° C. with 5% CO₂. The nextday, assay medium was exchanged with growth medium containing 1000 ng/mLof tetracycline (Fluka Analytical, Cat. #87128) to induce GPR40expression for 18-24 hours at 37° C. incubator with 5% CO₂. Afterinduction, the cells were washed with PBS (Gibco, Cat. #14190-036) anddetached with Cell Stripper (Cellgro, Cat. #25-056-CL). 10-20 mL growthmedium were added to the flask and cells were collected in 50 mL tubes(Falcon, Cat. #352098) and spun at 1000 RPM for 5 minutes. Culturemedium was aspirated and the cells were resuspended in 10 mL of 1×IP-OneStimulation Buffer from the Cisbio IP-One kit (Cisbio, Cat. #62IPAPEJ).The cells were diluted to 1.4×106 cells/mL in Stimulation Buffer.

Test compounds were 3-fold, 11-point serially diluted in DMSO in a REMPassay plate (Matrix Cat. #4307) by Biocel (Agilent). The compounds weretransferred into an Echo plate (Labcyte, Cat. #LP-0200) and 20 nL ofdiluted compounds were transferred to an assay plate (proxi-plate fromPerkin Elmer, Cat. #6008289) by Echo acoustic nano dispenser (Labcyte,model ECHO550). 14 μL of the diluted cells were then added to the assayplate by Thermo (SN 836 330) CombiDrop and incubated at room temperaturefor 45 minutes. Then 3 μL of IP1 coupled to dye D2 from the CisbioIP-One kit were added to the assay plate followed by 3 μL of Lumi4-Tbcryptate K from the kit. The plate was further incubated at room for 1hour before reading on the Envision (Perkin Elmer Model2101) with anHTRF protocol. Activation data for the test compound over a range ofconcentrations was plotted as percentage activation of the test compound(100%=maximum response). After correcting for background [(sampleread−mean of low control)/(mean of high control−mean of low control)](low control is DMSO without any compound), EC₅₀ values were determined.The EC₅₀ is defined as the concentration of test compound which produces50% of the maximal response and was quantified using the 4 parameterlogistic equation to fit the data. The maximal Y value observed (% Ymax)was calculated relative to a BMS standard reference compound at a finalconcentration of 0.625 μM.

Some of the exemplified Examples disclosed below were tested in theHuman GRP40 In Vitro assay described above and found having hGRP40modulating activity reported as hGPR40 IP1 EC₅₀.

The compounds of the present invention possess activity as modulators ofGPR40, and, therefore, may be used in the treatment of diseasesassociated with GPR40 activity. Via modulation of GPR40, the compoundsof the present invention may preferably be employed to modulate theproduction/secretion of insulin and/or gut hormones, such as GLP-1, GIP,CCK and amylin.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, gestational diabetes, insulin resistance, hyperinsulinemia,retinopathy, neuropathy, nephropathy, diabetic kidney disease, acutekidney injury, cardiorenal syndrome, acute coronary syndrome, delayedwound healing, atherosclerosis and its sequelae (acute coronarysyndrome, myocardial infarction, angina pectoris, peripheral vasculardisease, intermittent claudication, myocardial ischemia, stroke, heartfailure), Metabolic Syndrome, hypertension, obesity, fatty liverdisease, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, vascular restenosis, peripheralarterial disease, lipid disorders, liver diseases such as NASH(Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty LiverDisease) and liver cirrhosis, neurodegenerative disease, cognitiveimpairment, dementia, and treatment of side-effects related to diabetes,lipodystrophy and osteoporosis from corticosteroid treatment.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am.Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med.Chem.-Imm., Endoc. & Metab. Agents, 1:1-24 (2001).

GPR40 is expressed in neuronal cells, and is associated with developmentand maintenance of neuronal health in brain, as described in Yamashima,T., Progress in Neurobiology, 84:105-115 (2008).

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; buccally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, L. V., Jr. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., an antidiabetic agentor other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other GPR40 modulators or one or more other suitable therapeuticagents useful in the treatment of the aforementioned disordersincluding: anti-diabetic agents, anti-hyperglycemic agents,anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-atherosclerotic agents,anti-ischemic agents, anti-hypertensive agents, anti-obesity agents,anti-dyslipidemic agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,anorectic agents, and appetite suppressants.

Where desired, the compound of the present invention may be used incombination with one or more other types of antidiabetic agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of antidiabetic agent that may be optionallyemployed in combination with the GPR40 receptor modulator of the presentinvention may be one, two, three or more antidiabetic agents orantihyperglycemic agents which may be administered orally in the samedosage form, in a separate oral dosage form, or by injection to producean additional pharmacological benefit.

The antidiabetic agents used in the combination with the compound of thepresent invention include, but are not limited to, insulin secretagoguesor insulin sensitizers, other GPR40 receptor modulators, or otherantidiabetic agents. These agents include, but are not limited to,dipeptidyl peptidase IV inhibitors (DPP4i; for example, sitagliptin,saxagliptin, alogliptin, vildagliptin), biguanides (for example,metformin, phenformin), sulfonyl ureas (for example, gliburide,glimepiride, glipizide), glucosidase inhibitors (for example, acarbose,miglitol), PPARγ agonists such as thiazolidinediones (for example,rosiglitazone, pioglitazone), PPAR α/γ dual agonists (for example,muraglitazar, tesaglitazar, aleglitazar), glucokinase activators (asdescribed in Fyfe, M. C. T. et al., Drugs of the Future, 34(8):641-653(2009) and incorporated herein by reference), other GPR40 receptormodulators (e.g., TAK-875), GPR119 receptor modulators (for example,MBX-2952, PSN821, APD597), GPR120 receptor modulators (for example, asdescribed in Shimpukade, B. et al., J. Med. Chem., 55(9):4511-4515(2012)), sodium-glucose transporter-2 (SGLT2) inhibitors (for exampledapagliflozin, canagliflozin, empagliflozin, remagliflozin), 11b-HSD-1inhibitors (for example MK-0736, BI35585, BMS-823778, and LY2523199),MGAT inhibitors (for example, as described in Barlind, J. G. et al.,Bioorg. Med. Chem. Lett. (2013), doi: 10.1016/j.bmcl.2013.02.084),amylin analogs such as pramlintide, and/or insulin. Reviews of currentand emerging therapies for the treatment of diabetes can be found in:Mohler, M. L. et al., Medicinal Research Reviews, 29(1):125-195 (2009),and Mizuno, C. S. et al., Current Medicinal Chemistry, 15:61-74 (2008).

The GPR40 receptor modulator of formula I may also be optionallyemployed in combination with agents for treating complication ofdiabetes. These agents include PKC inhibitors and/or AGE inhibitors.

The GPR40 receptor modulator of formula I way also be optionallyemployed in combination with one or more hypophagic agents such asdiethylpropion, phendimetrazine, phentermine, orlistat, sibutramine,lorcaserin, pramlintide, topiramate, MCHR1 receptor antagonists,oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptor modulators,NPY Y2 receptor modulators, NPY Y4 receptor modulators, cetilistat,5HT2c receptor modulators, and the like. The compound of structure I mayalso be employed in combination with an agonist of the glucagon-likepeptide-1 receptor (GLP-1 R), such as exenatide, liraglutide,GPR-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S.Pat. No. 5,614,492 to Habener, the disclosure of which is incorporatedherein by reference), which may be administered via injection,intranasal, or by transdermal or buccal devices. Reviews of current andemerging therapies for the treatment of obesity can be found in:Melnikova, I. et al., Nature Reviews Drug Discovery, 5:369-370 (2006);Jones, D., Nature Reviews: Drug Discovery, 8:833-834 (2009); Obici, S.,Endocrinology, 150(6):2512-2517 (2009); and Elangbam, C. S., Vet.Pathol., 46(1):10-24 (2009).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the GPR40 receptor. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving GPR40 or anti-diabetic activity. For example, acompound of the present invention could be used as a reference in anassay to compare its known activity to a compound with an unknownactivity. This would ensure the experimentor that the assay was beingperformed properly and provide a basis for comparison, especially if thetest compound was a derivative of the reference compound. Whendeveloping new assays or protocols, compounds according to the presentinvention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving GPR40.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof,and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of multiple diseases or disordersassociated with GPR40 (as defined previously). In another embodiment,the package insert states that the pharmaceutical composition can beused in combination (as defined previously) with a second therapeuticagent for the treatment of multiple diseases or disorders associatedwith GPR40. The article of manufacture can further comprise: (d) asecond container, wherein components (a) and (b) are located within thesecond container and component (c) is located within or outside of thesecond container. Located within the first and second containers meansthat the respective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

Examples

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Compounds of this invention mayhave one or more asymmetric centers. Throughout the examples and theappended claims, a given chemical formula or name shall encompass allstereo and optical isomers and racemates thereof where such isomersexist. Unless otherwise indicated, all chiral (enantiomeric anddiastereomeric) and racemic forms are within the scope of the invention.

Abbreviations and chemical symbols have their usual and customarymeanings unless otherwise indicated. Unless otherwise indicated, thecompounds described herein have been prepared, isolated andcharacterized using the schemes and other methods disclosed herein ormay be prepared using the same.

HPLC/MS and Preparatory/Analytical HPLC Methods Employed inCharacterization or Purification of Examples

Analytical HPLC/MS (unless otherwise noted) was performed on ShimadzuSCL-10A liquid chromatographs and Waters MICROMASS® ZQ MassSpectrometers (Desolvation Gas: Nitrogen; Desolvation Temp. 250° C.; IonSource Temp: 120° C.; Positive Electrospray conditions) using thefollowing method

Linear Gradient of 0% to 100% solvent B over 2 min, with 1 minute holdat 100% B;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna C18 (2) 30 mm×4.60 mm; 5 m particle (Heated toTemp. 40° C.);

Flow rate: 5 ml/min;

Solvent A: 10% MeCN-90% H₂O-0.1% TFA; or, 10% MeOH-90% H₂O-0.1% TFA; and

Solvent B: 90% MeCN-10% H₂O-0.1% TFA; or, 90% MeOH-10% H₂O-0.1% TFA.

Preparatory HPLC (unless otherwise noted) was performed on a ShimadzuSCL-10A liquid chromatograph with a linear gradient of 20-100% Solvent Bover 10 or 30 min, with either a 2 or 5 min (respectively) hold at 100%Solvent B;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna Axia 5μ C18 30×100 mm;

Flow rate: 20 mL/min;

Solvent A: 10% MeCN-90% H₂O-0.1% TFA; and

Solvent B: 90% MeCN-10% H₂O-0.1% TFA.

Analytical HPLC (unless otherwise noted) was performed to determinecompound purity on a Shimadzu SIL-10A using the following method (Unlessotherwise stated, retention times listed in Examples refer the retentiontimes of Column 1)

Linear Gradient of 10% to 100% solvent B over 15 min;

UV visualization at 220 nm and 254 nm;

Column 1: SunFire C18 3.5 μm, 4.6×150 mm;

Column 2: XBridge Phenyl 3.5 μm, 4.6×150 mm;

Flow rate: 1 ml/min (for both columns);

Solvent A: 5% MeCN-95% H₂O-0.05% TFA; and

Solvent B: 95% MeCN-5% H₂O-0.05% TFA.

or

Linear Gradient of stated starting percentage to 100% solvent B over 8min;

UV visualization at 220 nm;

Column: ZORBAX® SB C18 3.5 μm, 4.6×75 mm;

Flow rate: 2.5 ml/min;

Solvent A: 10% MeOH-90% H₂O-0.2% H₃PO₄; and

Solvent B: 90% MeOH-10% H₂O-0.2% H₃PO₄.

NMR Employed in Characterization of Examples

¹H NMR spectra (unless otherwise noted) were obtained with JEOL® orBruker FOURIER® transform spectrometers operating at 400 MHz or 500 MHz.¹H-nOe experiments were performed in some cases for regiochemistryelucidation with a 400 MHz Bruker FOURIER® Transform spectrometer.

Spectral data are reported as chemical shift (multiplicity, number ofhydrogens, coupling constants in Hz) and are reported in ppm (6 units)relative to either an internal standard (tetramethylsilane=0 ppm) for ¹HNMR spectra, or are referenced to the residual solvent peak (2.49 ppmfor CD₃SOCD₂H, 3.30 ppm for CD₂HOD, 1.94 for CHD₂CN, 7.26 ppm for CHCl₃,5.32 ppm for CDHCl₂).

Example 12-((2S,3S,4R)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

1A. (R)-1-Benzyl 2-methyl4-((tert-butyldimethylsilyl)oxy)-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate

To a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate, HCl(10.0 g, 55.3 mmol) in CH₂Cl₂ (76 mL) at rt was added imidazole (8.66 g,127 mmol) and TBS-Cl (9.17 g, 60.8 mmol). The reaction mixture wasstirred at rt overnight. The reaction mixture was washed with 10% aq.Na₂CO₃ (75 mL). The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (75 mL). The combined organic layers wereconcentrated to a small volume and then toluene was added and thefractions were concentrated to ˜75 mL. The toluene phase was washed withwater and then used directly in the next step. To the solution of(2S,4R)-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylatein toluene cooled to 0° C. was added water (25 mL) followed by NaDCC(6.69 g, 30.4 mmol). After 30 min, the reaction mixture was filteredthrough CELITE®, washed with toluene (30 mL), and the phases wereseparated. The organic phase was washed with water, cooled to 0° C., andNEt₃ (9.3 mL, 66 mmol) was added. The reaction mixture was stirred for 1h at 0° C. and then overnight at rt. The organic solution was washedwith water (2×), dried (MgSO₄), and concentrated. The crude material wasused directly in the next step without further purification. To asolution of (R)-methyl3-((tert-butyldimethylsilyl)oxy)-3,4-dihydro-2H-pyrrole-5-carboxylate inCH₂Cl₂ (101 mL) at −10° C. was added 2,6-lutidine (11.8 mL, 101 mmol)followed by the dropwise addition of benzyl chloroformate (7.9 mL, 56mmol) and the reaction mixture was warmed to rt and stirred overnight.Ethylenediamine (0.50 mL, 7.4 mmol) was added to the reaction mixture,which was stirred for 15 min at rt and then washed with 1 N aq. citricacid (60 mL) and 1 N aq. HCl (50 mL). The organic layer was washed withwater, 1.5 N aq. KH₂PO₄, and brine. The organic layer was dried(Na₂SO₄), filtered, and concentrated. The crude product was purified bysilica chromatography to provide 1A (16.3 g, 41.6 mmol, 82% yield) as acolorless oil. LC-MS Anal. Calc'd for C₂₀H₂₉NO₅Si: 391.55, found [M+H]392.0. ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.29 (m, 5H), 5.69-5.62 (m, 1H),5.20-5.11 (m, 2H), 4.94 (dt, J=7.7, 3.2 Hz, 1H), 3.98 (dd, J=12.4, 8.0Hz, 1H), 3.79 (dd, J=12.2, 3.4 Hz, 1H), 3.71-3.62 (m, 3H), 0.88 (s, 9H),0.07 (d, J=3.3 Hz, 6H).

1B. (2R,3S,4R)-1-Benzyl 2-methyl4-((tert-butyldimethylsilyl)oxy)-3-methylpyrrolidine-1,2-dicarboxylate

CuBr.SMe₂ (4.78 g, 23.2 mmol) was suspended in anhydrous Et₂O (51 mL)and cooled to −40° C. A 1.6 M solution of MeLi in Et₂O (29.1 mL, 46.5mmol) was added dropwise via addition funnel. The solution was stirredfor 1 h and then a solution of 1A (7.00 g, 17.9 mmol) in Et₂O (20.4 mL)was added dropwise via addition funnel. The reaction mixture was stirredfor 45 min at −45° C. and then transferred via cannula to a vigorouslystirred solution of sat. aq. NH₄Cl and stirred for 30 min. The organiclayer was separated and washed with sat. aq. NH₄Cl. The combined aqueouslayers were extracted with hexanes. The combined organic layers weredried (MgSO₄) and concentrated. The crude material was purified bysilica chromatography to obtain 1B (5.11 g, 12.5 mmol, 70% yield) as acolorless oil. LC-MS Anal. Calc'd for C₂₁H₃₃NO₅Si: 407.58, found [M+H]408.2. ¹H NMR (500 MHz, CDCl₃) δ (two rotamers) 7.40-7.27 (m, 5H),5.21-5.00 (m, 2H), 4.01-3.90 (m, 1H), 3.87-3.80 (m, 1.6H), 3.77-3.71 (sand m, 1.8H), 3.57 (s, 1.6H), 3.36-3.28 (m, 1H), 2.33-2.25 (m, 1H), 1.11(dd, J=7.2, 2.2 Hz, 3H), 0.86 (s, 9H), 0.08-0.01 (m, 6H).

1C. (2R,3S,4R)-1-Benzyl 2-methyl4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate

To a solution of 1B (5.10 g, 12.5 mmol) in THF (42 mL) was added a 1 Msolution of TBAF in THF (19 mL, 19 mmol) and the reaction mixture wasstirred at rt for 1 h. The reaction mixture was diluted with EtOAc andwashed with water and brine, dried (MgSO₄), and concentrated. The crudematerial was purified by silica chromatography to obtain 1C (3.61 g,12.3 mmol, 98% yield) as a colorless oil, which crystallized to a whitesolid upon standing. LC-MS Anal. Calc'd for C₁₅H₁₉NO₅: 293.32, found[M+H] 294.0. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.27 (m, 5H), 5.25-4.97 (m,2H), 4.09-3.96 (m, 1H), 3.95-3.87 (m, 1H), 3.86-3.70 (m, 3H), 3.69-3.57(m, 2H), 3.10-2.83 (m, 1H), 2.37 (td, J=6.9, 2.9 Hz, 1H), 1.12 (d, J=7.3Hz, 3H).

1D. (2R,3S,4R)-1-Benzyl 2-methyl4-(allyloxy)-3-methylpyrrolidine-1,2-dicarboxylate

To a solution of 1C (0.405 g, 1.38 mmol) in DMF (6.9 mL) at 0° C. wasadded 60% NaH (0.083 g, 2.1 mmol). The reaction mixture was stirred for30 min and then allyl bromide (0.18 mL, 2.1 mmol) was added. Thereaction mixture was warmed to rt and stirred for 1 h. The reactionmixture was quenched with water and diluted with EtOAc. The layers wereseparated and the organic layer was washed with water (4×). The organiclayer was washed with brine, dried (MgSO₄), and concentrated. The crudeproduct was purified by silica chromatography to provide 1D (0.446 g,1.34 mmol, 97% yield) as a colorless oil. LC-MS Anal. Calc'd forC₁₈H₂₃NO₅: 333.38, found [M+H]334.0. ¹H NMR (500 MHz, CDCl₃) δ (tworotamers) 7.41-7.27 (m, 5H), 5.90-5.77 (m, 1H), 5.29-4.99 (m, 4H),4.09-3.90 (m, 3H), 3.86 and 3.80 (2 dd, J=11.3, 5.6 Hz, 1H), 3.73 and3.57 (2 s, 3H), 3.67-3.61 (m, 1H), 3.46 (ddd, J=11.0, 6.1, 4.7 Hz, 1H),2.59-2.44 (m, 1H), 1.14 (dd, J=7.2, 1.1 Hz, 3H).

1E. (2R,3S,4R)-1-Benzyl 2-methyl4-(3-hydroxypropoxy)-3-methylpyrrolidine-1,2-dicarboxylate

To a solution of 1D (2.74 g, 8.20 mmol) in THF (4.1 mL) at 0° C. wasadded a 1 M solution of BH₃.THF (2.8 mL, 2.8 mmol) in THF. After 15 min,the reaction mixture was stirred at rt for 2.2 h. Additional BH₃.THF (1M in THF) (0.2 mL, 0.2 mmol) was added and the reaction mixture wasstirred for an additional 15 min. Water (4.1 mL) and sodiumperborate-4H₂O (1.29 g, 8.37 mmol) were added. After stirring for 2 h,the reaction mixture was diluted with EtOAc, washed with brine, dried(MgSO₄), and concentrated. The crude product was purified by silicachromatography to provide 1E (2.17 g, 6.18 mmol, 75% yield) as acolorless oil. LC-MS Anal. Calc'd for C₁₈H₂₅NO₆: 351.39, found [M+H]352.0. ¹H NMR (500 MHz, CDCl₃) δ (two rotamers) 7.43-7.27 (m, 5H),5.26-5.00 (m, 2H), 4.18-3.98 (m, 1H), 3.84-3.76 (m, 1H), 3.75 and 3.61(two s, 3H), 3.73-3.66 (m, 2H), 3.61-3.50 (m, 4H), 2.62-2.50 (m, 1H),2.04-2.00 (m, 1H), 1.77 (quind, J=5.7, 2.9 Hz, 2H), 1.12 (d, J=7.2 Hz,3H).

1F. (2R,3S,4R)-1-Benzyl 2-methyl4-(3-methoxypropoxy)-3-methylpyrrolidine-1,2-dicarboxylate

To a solution of 1E (2.17 g, 6.18 mmol) in MeCN (7.7 mL) was added Ag₂O(3.58 g, 15.4 mmol) and MeI (3.9 mL, 62 mmol). The reaction mixture wasstirred at 50° C. for 18 h. The mixture was filtered and concentrated.The crude product was purified by silica chromatography to provide 1F(2.71 g, 7.42 mmol, 81% yield). LC-MS Anal. Calc'd for C₁₉H₂₇NO₆:365.42, found [M+H] 367.0. ¹H NMR (500 MHz, CDCl₃) δ 7.41-7.27 (m, 5H),5.24-4.99 (m, 2H), 4.08-3.94 (m, 1H), 3.89-3.76 (m, 1H), 3.73, 3.58 (2s, 3H), 3.57-3.53 (m, 1H), 3.51-3.42 (m, 3H), 3.40 (t, J=6.2 Hz, 2H),3.32, 3.3 (2 s, 3H), 2.49 (dtd, J=6.9, 4.7, 2.2 Hz, 1H), 1.76 (quind,J=6.3, 2.1 Hz, 2H), 1.13 (dd, J=7.2, 3.0 Hz, 3H).

1G. (2R,3S,4R)-Benzyl2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyrrolidine-1-carboxylate

To a solution of 1F (4.13 g, 11.3 mmol) in THF (57 mL) at 0° C. wasadded a 2 M solution of LiBH₄ (11.3 mL, 22.6 mmol) in THF. The reactionmixture was warmed to rt and stirred for 17 h. The reaction mixture wascooled to 0° C., carefully quenched with sat. aq. NH₄Cl, and dilutedwith EtOAc/water. The layers were separated and the organic layer waswashed with brine, dried (MgSO₄), and concentrated. The crude productwas purified by silica chromatography to provide 1G (3.25 g, 9.15 mmol,81%) as a colorless oil. LC-MS Anal. Calc'd for C₁₈H₂₇NO₅: 337.41, found[M+H] 338.0. ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.28 (m, 5H), 5.14 (s, 2H),4.41-4.31 (m, 1H), 3.85-3.70 (m, 3H), 3.69-3.61 (m, 1H), 3.57-3.47 (m,3H), 3.46-3.39 (m, 2H), 3.34-3.26 (m, 3H), 2.06-1.94 (m, 1H), 1.81(quin, J=6.4 Hz, 2H), 1.09 (dd, J=9.9, 7.2 Hz, 3H).

1H. ((2R,3S,4R)-4-(3-Methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol

A mixture of 1G (3.25 g, 9.63 mmol) and Pd/C (0.820 g, 0.771 mmol) inMeOH (193 mL) was purged with argon (3×) and then H₂ (3×). The reactionmixture was stirred under H₂ (1 atm) at rt for 3.5 h. The mixture wasfiltered through CELITE® and concentrated to give 1H (2.03 g, 9.99 mmol,100% yield). LC-MS Anal. Calc'd for C₁₀H₂₁NO₃: 203.28, found [M+H]204.1. ¹H NMR (500 MHz, CDCl₃) δ 3.63 (dd, J=11.1, 3.4 Hz, 1H),3.55-3.49 (m, 2H), 3.47 (t, J=6.3 Hz, 2H), 3.43 (td, J=6.3, 2.1 Hz, 2H),3.31 (s, 3H), 3.06-3.00 (m, 1H), 2.98-2.90 (m, 1H), 2.85-2.76 (m, 1H),1.85 (dt, J=6.9, 3.4 Hz, 1H), 1.83-1.75 (m, 2H), 1.05 (d, J=7.2 Hz, 3H).

1I. 4-Bromo-2-methoxypyridine

A heterogeneous reaction mixture of 4-bromo-2-fluoropyridine (2.64 mL,25.6 mmol) and NaOMe (8.29 g, 153 mmol) in MeOH (36.5 mL) was reacted ina pressure tube at 155° C. for 5 h. The reaction mixture was cooled tort and the solids were filtered and washed with EtOAc. The filtrate wasconcentrated to a pale yellow oil with some white solids. The oil yellowwas decanted and diluted with water and the solution was extracted withEtOAc (2×). The combined organic layers were washed with water andbrine, dried over MgSO₄, filtered, and concentrated to obtain 11 (4.43g, 21.20 mmol, 83% yield) as a yellow oil. LC-MS Anal. Calc'd forC₆H₆BrNO: 188.02, found [M+H] 187.9, 189.9. ¹H NMR (400 MHz, CDCl₃) δ7.98 (d, J=5.5 Hz, 1H), 7.02 (dd, J=5.5, 1.5 Hz, 1H), 6.94 (d, J=1.8 Hz,1H), 3.92 (s, 3H).

1J. 4-Bromo-5-chloro-2-methoxypyridine

To a solution of 1I (2.00 g, 10.6 mmol) in DMF (21 mL) was added NCS(2.98 g, 22.3 mmol). The reaction mixture was stirred at rt overnight.The reaction mixture was quenched with water, diluted with EtOAc, andthe layers were separated. The aqueous layer was extracted with EtOAcand the combined organic extracts were washed with brine, dried overMgSO₄, and concentrated. The crude product was purified by silicachromatography to provide 1J (2.15 g, 9.18 mmol, 86% yield) as a whitesolid. LC-MS Anal. Calc'd for C₆H₅BrClNO: 220.92, found [M+H] 223.8. ¹HNMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.05 (s, 1H), 3.91 (s, 3H).

1K. (3,4-cis)-1-Benzyl-3-methylpiperidin-4-ol

To a solution of 1-benzyl-3-methylpiperidin-4-one (24.8 g, 122 mmol) inTHF (102 mL) at −78° C. was added dropwise a 1 M solution ofL-Selectride (183 mL, 183 mmol) in THF. The reaction mixture was stirredat −78° C. for 90 min. EtOH (22 mL), water (55 mL), and 1 M aq. NaOH (55mL) were added sequentially. The reaction mixture was warmed to 0° C.and 30% aq. H₂O₂(55 mL) was added dropwise. The cold bath was removedand the reaction mixture was stirred at rt for 2 h. The reaction mixturewas diluted with EtOAc and the insoluble white solid was discarded. Theorganic layer was washed with sat. aq. NaHCO₃ and brine, dried (MgSO₄),and concentrated to give the crude product as an oil. Purification viasilica chromatography gave 1K as a white solid (22.2 g, 88% yield).LC-MS Anal. Calc'd for C₁₃H₁₉NO: 205.30, found [M+H] 206.2. ¹H NMR (500MHz, CDCl₃) δ 7.40-7.20 (m, 5H), 3.84 (s, 1H), 3.55 (s, 2H), 2.60-1.73(m, 7H), 0.97 (d, 3H).

1L.(3,4-cis)-1-Benzyl-4-((tert-butyldimethylsilyl)oxy)-3-methylpiperidine

To a solution of 1K (21.86 g, 106.5 mmol) and NEt₃ (44.5 mL, 320 mmol)in CH₂Cl₂ (107 mL) at 0° C. was added TBSOTf (29.4 mL, 128 mmol). Thereaction mixture was stirred at 0° C. for 1 h. Sat. aq. NaHCO₃ (180 mL)was added slowly to the reaction mixture. The mixture was concentrated,diluted with EtOAc, washed with water and brine, dried (MgSO₄), andconcentrated. Purification via silica chromatography gave 1L as an oil(31.48 g, 92% yield). LC-MS Anal. Calc'd for C₁₉H₃₃NOSi: 319.56, found[M+H]320.3.

1M. (3,4-cis)-4-((tert-Butyldimethylsilyl)oxy)-3-methylpiperidine

A mixture of 1L (15.7 g, 49.3 mmol) and 10% Pd/C (3.15 g) in MeOH (493mL) was purged with argon (3×) and H₂ (3×). The reaction mixture wasstirred under H₂ (1 atm) at rt for 24 h. The mixture was filteredthrough CELITE® and the filtrate was concentrated to give 1M (11.3 g,49.3 mmol, 100% yield). ¹H NMR (500 MHz, CDCl₃) δ 3.80 (s, 1H), 2.90 (m,1H), 2.70-2.50 (m, 4H), 1.60-1.50 (m, 3H), 0.86 (s, 9H), 0.80 (d, 3H),0.00 (s, 6H).

1N.4-((3,4-cis)-4-((tert-Butyldimethylsilyl)oxy)-3-methylpiperidin-1-yl)-5-chloro-2-methoxypyridine

A mixture of 1J (9.70 g, 43.6 mmol), 1M (10.0 g, 43.6 mmol), and K₂CO₃(12.0 g, 87.0 mmol) in DMSO (14.5 mL) was vigorously stirred at 110° C.overnight. The reaction mixture was diluted with water and extractedwith EtOAc. The organic layer was washed with water and brine, dried(MgSO₄), and concentrated. Purification via silica chromatography gave1N as an oil (14.3 g, 38.6 mmol, 77% yield). LC-MS Anal. Calc'd forC₁₈H₃₁ClN₂O₂Si: 370.18, found [M+H] 371.2. ¹H NMR (400 MHz, CDCl₃) δ7.94 (s, 1H), 6.27 (s, 1H), 3.90-3.85 (m, 4H), 3.25 (dtd, J=11.7, 3.9,1.8 Hz, 1H), 3.14-3.02 (m, 2H), 2.84 (t, J=11.0 Hz, 1H), 2.00-1.88 (m,1H), 1.88-1.81 (m, 1H), 1.80-1.71 (m, 1H), 0.94-0.89 (m, 12H), 0.06 (s,6H).

1O. (3,4-cis)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol

To a solution of 10 (10.0 g, 27.0 mmol)) in THF (27 mL) was added a 1 Msolution of TBAF in THF (81 mL, 81 mmol). The reaction mixture wasstirred at 23° C. for 16 h. Sat. aq. NaHCO₃ (100 mL) was added slowly tothe reaction mixture. The mixture was extracted with EtOAc (2×100 mL)and the combined organic extracts were washed with water (50 mL) andbrine (50 mL), dried (Na₂SO₄), filtered, and concentrated. Purificationvia silica chromatography gave 10 as white foam (7.00 g, 27.0 mmol, 99%yield). LC-MS Anal. Calc'd for C₁₂H₁₇ClN₂O₂: 256.10, found [M+H] 257.0.¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 6.27 (s, 1H), 3.98-3.91 (m, 1H),3.88 (s, 3H), 3.26-3.18 (m, 1H), 3.16-3.06 (m, 2H), 2.90 (dd, J=11.7,9.9 Hz, 1H), 2.11-2.00 (m, 1H), 2.00-1.84 (m, 2H), 1.40 (d, J=3.7 Hz,1H), 1.03 (d, J=6.8 Hz, 3H).

1P. (3,4-cis)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol,Isomer 1 and Isomer 2

10 (8.8 g, 34.2 mmol) was separated by chiral SFC to give 1P as singleisomers. 1P, Isomer 1 (3.00 g, 11.7 mmol, 34% yield) was isolated as acolorless oil. LC-MS Anal. Calc'd for C₁₂H₁₇ClN₂O₂: 256.10, found [M+H]257.0. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 6.27 (s, 1H), 3.97-3.91(m, 1H), 3.88 (s, 3H), 3.27-3.17 (m, 1H), 3.16-3.04 (m, 2H), 2.90 (dd,J=11.7, 9.9 Hz, 1H), 2.05 (dd, J=6.9, 2.9 Hz, 1H), 2.00-1.83 (m, 2H),1.42 (d, J=3.8 Hz, 1H), 1.03 (d, J=7.0 Hz, 3H). 1P, Isomer 2 (3.00 g,11.7 mmol, 34% yield) was isolated as a colorless oil. LC-MS Anal.Calc'd for C₁₂H₁₇ClN₂O₂: 256.10, found [M+H] 257.0. ¹H NMR (400 MHz,CDCl₃) δ 7.96 (s, 1H), 6.27 (s, 1H), 3.97-3.91 (m, 1H), 3.88 (s, 3H),3.27-3.17 (m, 1H), 3.16-3.04 (m, 2H), 2.90 (dd, J=11.7, 9.9 Hz, 1H),2.05 (dd, J=6.9, 2.9 Hz, 1H), 2.00-1.83 (m, 2H), 1.42 (d, J=3.8 Hz, 1H),1.03 (d, J=7.0 Hz, 3H).

1Q.5-Chloro-4-((3,4-trans)-4-(4-iodophenoxy)-3-methylpiperidin-1-yl)-2-methoxypyridine

To a solution of 1P, Isomer 1 (0.519 g, 2.02 mmol), 4-iodophenol (0.579g, 2.63 mmol), and Bu₃P (0.80 mL, 3.2 mmol) in toluene (25 mL) was addedADDP (0.817 g, 3.24 mmol). The reaction mixture was sonicated for 99min. The reaction mixture was poured into hexanes, filtered, andconcentrated. The crude product was purified by silica chromatography toprovide 1Q (0.482 g, 1.05 mmol, 52% yield) as a colorless oil. LC-MSAnal. Calc'd for C₁₈H₂₀ClIN₂O₂: 458.72, found [M+H] 459.0. ¹H NMR (400MHz, CDCl₃) δ 7.98 (s, 1H), 7.61-7.50 (m, 2H), 6.75-6.66 (m, 2H), 6.27(s, 1H), 3.99-3.90 (m, 1H), 3.89 (s, 3H), 3.56-3.46 (m, 2H), 2.93-2.82(m, 1H), 2.65 (dd, J=12.3, 9.0 Hz, 1H), 2.23-2.08 (m, 2H), 1.82 (dtd,J=13.1, 9.7, 3.9 Hz, 1H), 1.10 (d, J=6.6 Hz, 3H).

1R.((2R,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol

1Q (0.191 g, 0.416 mmol), 1H (0.0770 g, 0.379 mmol), CuI (0.014 g, 0.076mmol), and NaOH (0.045 g, 1.1 mmol) were combined in a microwave tube,which was purged with argon. n-BuOH (1.9 mL) was added and the reactionmixture was heated to 90° C. overnight. The reaction mixture was cooledto rt and quenched with sat. aq. NH₄Cl. The product was extracted withCH₂Cl₂ (3×). The combined organic layers were washed with brine, dried(MgSO₄), and concentrated. The crude product was purified by silicachromatography to provide 1R (0.144 g, 0.269 mmol, 71% yield) as anamber oil. LC-MS Anal. Calc'd for C₂₈H₄₀ClN₃O₅: 534.09, found [M+H]534.2. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 6.86 (d, J=9.0 Hz, 2H),6.59 (d, J=9.0 Hz, 2H), 6.26 (s, 1H), 3.95-3.89 (m, 1H), 3.88 (s, 3H),3.77 (td, J=8.6, 4.1 Hz, 1H), 3.74-3.67 (m, 2H), 3.65-3.54 (m, 3H),3.54-3.49 (m, 3H), 3.48-3.40 (m, 3H), 3.33 (s, 3H), 2.86-2.77 (m, 2H),2.62 (dd, J=12.1, 9.2 Hz, 1H), 2.46 (q, J=7.3 Hz, 1H), 2.20-2.07 (m,2H), 1.89-1.75 (m, 3H), 1.14 (d, J=6.6 Hz, 3H), 1.05 (d, J=7.3 Hz, 3H).

1S.2-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetonitrile

1R (0.144 g, 0.269 mmol) was dissolved in CH₂Cl₂ (2.7 mL) and thesolution was cooled to 0° C. MsCl (0.031 mL, 0.40 mmol) and NEt₃ (0.075mL, 0.54 mmol) were added sequentially and the reaction mixture wasstirred at 0° C. for 40 min. The reaction mixture was diluted with EtOAcand washed with 1 N aq. HCl, sat. aq. NaHCO₃, and brine. The organiclayer was dried (MgSO₄) and concentrated. The crude product wasredissolved in DMSO (2.7 mL) and NaCN (0.053 g, 1.1 mmol) was added. Thereaction mixture was stirred at 50° C. overnight. The reaction mixturewas cooled to rt and quenched with water. The product was extracted withEtOAc (3×). The combined organic layers were washed with brine, dried(MgSO₄), and concentrated. The crude product was purified by silicachromatography to provide 1S (0.1294 g, 0.238 mmol, 88% yield) as acolorless oil. LC-MS Anal. Calc'd for C₂₉H₃₉ClN₄O₄: 543.10, found [M+H]543.2. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 6.90 (d, J=9.0 Hz, 2H),6.49 (d, J=9.0 Hz, 2H), 6.26 (s, 1H), 3.89 (s, 3H), 3.83-3.72 (m, 2H),3.69 (dd, J=9.1, 3.4 Hz, 1H), 3.63-3.46 (m, 6H), 3.44 (t, J=6.2 Hz, 2H),3.35-3.32 (m, 3H), 2.90-2.71 (m, 3H), 2.68-2.49 (m, 2H), 2.22-2.08 (m,2H), 1.89-1.74 (m, 3H), 1.14 (d, J=6.6 Hz, 3H), 1.05 (d, J=7.3 Hz, 3H).

1T.2-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetate

A ˜3 M HCl/MeOH/CH₂Cl₂ solution [25.2 mL, prepared by addition of AcCl(5.2 mL) to a 3/2 CHCl₂/MeOH solution (20 mL) at 0° C. and then stirringat rt for 20 min] was added to 1S (0.129 g, 0.238 mmol). The resultingsolution was allowed to stand at rt for 72 h. The reaction mixture wasconcentrated and rotovapped down with MeOH (2×). Then a ˜3M HCl/MeOHsolution [25.2 mL, prepared by addition of AcCl (5.2 mL) to a 3/2CHCl₂/MeOH solution (20 mL) at 0° C. and then stirring at rt for 20 min]was added to the residue, which was heated to 40° C. overnight withoutstirring. The reaction mixture was concentrated and neutralized withsat. aq. Na₂CO₃. The product was extracted with CH₂Cl₂ (3×). Thecombined organic layers were washed with brine, dried (MgSO₄), andconcentrated. The crude product was purified by silica chromatographyfollowed by RP-Prep HPLC and neutralized with sat. aq. NaHCO₃ to provide1T (0.0809 g, 0.140 mmol, 59% yield) as a colorless oil. LC-MS Anal.Calc'd for C₃₀H₄₂ClN₃O₆: 576.12, found [M+] 576.3. ¹H NMR (500 MHz,CDCl₃) δ 7.97 (s, 1H), 6.88 (d, J=9.1 Hz, 2H), 6.51 (d, J=9.1 Hz, 2H),6.26 (s, 1H), 3.88 (s, 3H), 3.80-3.74 (m, 2H), 3.72 (br. s, 1H), 3.71(s, 3H), 3.60-3.48 (m, 4H), 3.47-3.42 (m, 4H), 3.34-3.31 (m, 3H),2.85-2.77 (m, 2H), 2.75-2.67 (m, 1H), 2.62 (dd, J=12.4, 9.4 Hz, 1H),2.36 (q, J=7.4 Hz, 1H), 2.19-2.08 (m, 2H), 1.87-1.76 (m, 3H), 1.14 (d,J=6.6 Hz, 3H), 1.01 (d, J=7.4 Hz, 3H).

Example 1

To a solution of 1T (0.0809 g, 0.140 mmol) in THF (3.9 mL), i-PrOH (0.39mL), and water (0.39 mL) was added 1 M aq. LiOH (0.70 mL, 0.70 mmol).The reaction mixture was stirred at rt overnight. The reaction mixturewas mostly concentrated and then diluted with water/hexanes. The layerswere separated and the aqueous layer was acidified to pH 2 with 1 M aq.HCl. The product was extracted with CH₂Cl₂ (3×). The combined organiclayers were dried (MgSO₄) and concentrated to provide Example 1 (0.0773g, 0.136 mmol, 97% yield) as a white foam as a single isomer. LC-MSAnal. Calc'd for C₂₉H₄₀ClN₃O₆: 562.10, found [M+] 562.2. ¹H NMR (500MHz, CD₂Cl₂) δ 7.95 (s, 1H), 6.89 (d, J=9.1 Hz, 2H), 6.63 (d, J=8.8 Hz,2H), 6.29 (s, 1H), 3.86 (s, 3H), 3.81 (td, J=8.7, 4.0 Hz, 1H), 3.75-3.70(m, 1H), 3.65 (br. s, 1H), 3.60-3.54 (m, 1H), 3.54-3.40 (m, 7H), 3.30(s, 3H), 2.87-2.80 (m, 1H), 2.80-2.68 (m, 2H), 2.63 (dd, J=12.1, 9.4 Hz,1H), 2.39-2.32 (m, J=7.2 Hz, 1H), 2.20-2.13 (m, 1H), 2.13-2.05 (m, 1H),1.86-1.79 (m, 2H), 1.79-1.72 (m, 1H), 1.12 (d, J=6.6 Hz, 3H), 1.04 (d,J=7.2 Hz, 3H). Analytical HPLC: RT=10.0 min, HI: 98.9%. hGPR40 EC₅₀=56nM. hGPR40 IP1 EC₅₀=5 nM.

1U. (3R,4R)-1-Benzyl-3-methylpiperidin-4-ol

A 20 L reactor was sequentially rinsed with 2.0 L of MeOH and 2.0 L ofMILLI-Q® water. The reactor was charged with 1.0 kg of1-benzyl-3-methylpiperidin-4-one and 7.8 L of water under a nitrogenatmosphere at 25° C. The vessel was charged with 1.2 kg ofD-(+)-glucose, 1.0 L of pH 7.0 phosphate buffer, and 0.5 L of pH 7.4tris-chloride buffer. The mixture was stirred for 10 min. To thesolution was added 6.64 g of nicotinamide adenine dinucleotide and 20 gof glucose dehydrogenase (GDH-105, Codexis). The reaction temperaturewas gradually raised to 30° C. and the solution was agitated for 36 h.The reaction mixture was cooled to 10° C. and the pH was adjusted to 11with NaOH. The resulting solution was stirred for 1 h and then filteredthough a 10 m filter cloth. The solids were washed with water andallowed to suction dry for 3 h. The residue was dissolved in 20 L ofMTBE and the insoluble material was removed via filtration. The organiclayer was concentrated to 3.0 kg weight and 5.0 L of heptane was added.The solution was concentrated at 45° C. to 5 kg weight followed bystirring for 1 h during crystallization. The mixture was filtered andthe solids were dried to give 0.785 kg (78% yield) of 1U as a paleyellow solid. LC-MS Anal. Calc'd for C₁₃H₁₉NO: 205.30, found [M+H]206.1. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.24 (m, 5H), 3.48 (s, 2H),3.14-3.13 (m, 1H), 2.88-2.77 (m, 2H), 2.05 (dd, J=2.8, 12 Hz, 1H),1.99-1.87 (m, 1H), 1.73-1.58 (m, 4H), 0.95 (d, J=6.4, 3H).

1V. (3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol,MSA salt

MeOH (23.9 kg) was charged into a 250 L hydrogenator. 1U (2.92 kg) wasdissolved in MeOH (14.6 kg) and charged into the above hydrogenator.Nitrogen gas pressure (0.5 kg/cm²) was applied. The reaction mixture wasstirred for 5 min followed by the release of nitrogen gas pressure. Thisoperation was repeated (3×). A slurry of 10% Pd(OH)₂ (290 g) in MeOH(10.8 L) was charged into the above hydrogenator at rt. Nitrogen gaspressure (0.5 kg/cm²) was applied. The reaction mixture was stirred for5 min followed by the release of nitrogen gas pressure. This operationwas repeated (3×). Acetic acid (0.15 L) and MeOH (4.0 L) were chargedinto the above hydrogenator. Nitrogen gas pressure (0.5 kg/cm²) wasapplied. The reaction mixture was stirred for 5 min followed by therelease of nitrogen gas pressure. This operation was repeated (3×). Thehydrogenator was pressurized with 4.7 kg/cm² of hydrogen gas pressure.The reaction mixture was stirred under 4.0-5.0 kg/cm² of hydrogen gaspressure at ambient temperature (20-35° C.) for 16 h. The hydrogen gaspressure was released. Nitrogen gas pressure (0.5 kg/cm²) was applied tothe hydrogenate. The reaction mixture was stirred for 5 min followed bythe release of nitrogen gas pressure. This operation was repeated (4×).The reaction mixture was filtered through CELITE® and washed with MeOH(69.29 kg). The combined filtrates were charged through a cartridgefilter into a hallar lined reactor and concentrated to 9 L under vacuum,maintaining the temperature below 60° C. Toluene (25.31 kg) was chargedand the crude product was concentrated, maintaining the temperaturebelow 60° C. This procedure was repeated (2×). Dimethyl sulfoxide (25.5kg) was charged into the above reactor, maintaining the temperaturebelow 70° C. and the reaction mixture was concentrated to 26.5 L undervacuum, maintaining the temperature below 70° C. The reaction mixturewas cooled to rt. 1J (3.8 kg, 1.2 eq) and K₂CO₃ (7.0 kg, 3.5 eq) werecharged into the above reaction mixture at ambient temperature (20-35°C.). The reaction mixture was heated to 115-120° C. for 20 h. Thereaction mixture was cooled to ambient temperature (below 30° C.). Water(53.0 kg) was added into reaction mixture while maintaining thetemperature below 30° C. and the reaction mixture was stirred for 30min. EtOAc (21.0 kg) was charged and the reaction mixture was stirredfor 15 min. The layers were separated. EtOAc (21.0 kg) was added to theaqueous layer and the mixture was stirred for 15 min. The layers wereseparated. To the combined organic layers was added 1.5 N aq. HCl (18kg) and the mixture was stirred for 10 min. The layers were separated.To the organic layer was added 1.5 N aq. HCl (12.55 kg) and the solutionwas stirred for 10 min. The layers were separated. The combined acidicaqueous layers were basified to pH 8.1 from pH 0.8 by charging 10% aq.NaHCO₃ (16.5 kg). To the aqueous solution was added EtOAc (26.2 kg) andthe solution was stirred for 10 min. The layers were separated. Thisprocedure was repeated (2×). To the combined organic layers was added 34wt % aq. NaCl (15 kg) and the mixture was stirred for 10 min. The layerswere separated and the organic layer was dried over Na₂SO₄ (292 g),filtered through a nutsche filter, and the filtrate was charged intohallar lined reactor. The mixture was concentrated to 15 L under vacuummaintaining the temperature below 60° C. to obtain a dark brown viscousliquid. EtOAc (26.2 kg) was charged into the above reactor, maintainingthe temperature below 60° C. EtOAc swapping was continued until thewater content reached <1.0% by KF titration. The reaction mixture wascooled to 45-50° C. A solution of MSA (1.5 kg, 1.1 eq.) in EtOAc (14.0kg) was added to the reaction mixture at 45-50° C. over 1 h. Thereaction mixture was stirred for 20 min at 45-50° C. The reactionmixture was cooled to ambient temperature (20-35° C.) and stirred for 30min. The reaction mixture was filtered through a pressure nutsche filterand the solid was washed with EtOAc (6.0 L) and suction dried for 20min. The product was then dried under at 50-55° C. under vacuum for 15 hto obtain 1V (2.89 kg, 56% yield) as a pale brown solid. ¹H NMR (400MHz, DMSO) δ 8.08 (s, 1H), 6.42 (s, 1H), 3.87 (s, 3H), 3.64-3.43 (m,2H), 3.22-3.09 (m, 1H), 2.92-2.78 (m, 1H), 2.59-2.51 (m, 1H), 2.44 (s,3H), 1.95-1.83 (m, 1H), 1.66-1.42 (m, 2H), 0.94 (d, J=7.0 Hz, 3H).

1W.5-Chloro-2-methoxy-4-((3R,4R)-3-methyl-4-(4-nitrophenoxy)piperidin-1-yl)pyridine

A stirred solution of 1V (100 g, 283 mmol) in water (500 mL) and EtOAc(500 mL) was basified with 10% aq. NaHCO₃ to adjust the pH to ˜7.5. Thereaction mixture was stirred for 15 min at rt. The layers were separatedand the aqueous layer was extracted with EtOAc (200 mL). The combinedorganic layers were washed with water (250 mL) and brine (200 mL), driedover anhydrous Na₂SO₄, and concentrated to obtain crude(3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (74g), which was used without further purification. To a stirred solutionof (3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (74g) in THF (1.25 L) under a nitrogen atmosphere was added a 1 M solutionof KOtBu in THF (595 mL, 595 mmol) dropwise at 27° C. over 15 min. Asolution of 1-fluoro-4-nitrobenzene (44.0 g, 312 mmol) in THF (250 mL)was added dropwise into the reaction mixture over 15 min. The reactionmixture was stirred for 1 h at 27° C. The reaction was quenched withwater (3.0 L) and the product was extracted with EtOAc (2×2.0 L). Thecombined organic layers were washed with brine (500 mL), dried (Na₂SO₄),and concentrated. The crude product was purified by silicachromatography to afford 1W (80.0 g, 210 mmol, 74% yield) as a yellowsolid. LC-MS Anal. Calc'd for C₁₈H₂₀ClN₃O₄: 377.11, found [M+H] 378.0.¹H NMR (400 MHz, CDCl₃) δ 8.28-8.17 (m, 2H), 8.02 (s, 1H), 7.09-6.88 (m,2H), 6.31 (s, 1H), 4.17 (td, J=8.5, 4.1 Hz, 1H), 3.92 (s, 3H), 3.56 (dq,J=12.3, 1.9 Hz, 2H), 2.96 (ddd, J=12.5, 10.1, 2.9 Hz, 1H), 2.72 (dd,J=12.4, 9.1 Hz, 1H), 2.35-2.18 (m, 2H), 1.96-1.83 (m, 1H), 1.15 (d,J=6.6 Hz, 3H).

1X.4-((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yloxy)aniline

To a suspension of 1W (6.23 g, 16.5 mmol) in MeOH (100 mL) was addedNH₄Cl (8.82 g, 165 mmol) and water (25 mL), followed by iron powder (4.6g, 82 mmol). The suspension was purged with a stream of nitrogen for 2min and then vigorously stirred at 95° C. for 2 h. After cooling to rt,the reaction mixture became a thick black slurry, which was filtered viaa pad of CELITE®. The pad was washed with MeOH and EtOAc and thecombined filtrates were concentrated to remove most of the MeOH. Theremaining aqueous phase was extracted with EtOAc (3×). The combinedorganic extracts were washed with water and brine, dried (Na₂SO₄), andconcentrated. The obtained residue was dried under high vacuum for 2 hto afford 1× (5.73 g, 16.3 mmol, 99% yield) as a light brown foam. LC-MSAnal. Calc'd for C₁₈H₂₂ClN₃O₂: 347.14, found [M+H] 348.1. ¹H NMR (400MHz, CDCl₃) δ 7.99 (s, 1H), 6.90-6.76 (m, 2H), 6.71-6.59 (m, 2H), 6.29(s, 1H), 4.15 (d, J=7.0 Hz, 1H), 3.91 (s, 3H), 3.81 (td, J=8.6, 4.1 Hz,1H), 3.60-3.47 (m, 3H), 2.91-2.77 (m, 1H), 2.67-2.59 (m, 1H), 2.22-2.11(m, 2H), 1.82 (dd, J=13.1, 2.8 Hz, 1H), 1.16 (d, J=6.8 Hz, 3H).

1Z. (R)-4-Benzyl-3-((2R,3R)-3-hydroxy-4,4-dimethoxy-2-methylbutanoyl)oxazolidin-2-one

To a 1 L flask was added a 60% aq. solution of 2,2-dimethoxyacetaldehyde(250 g, 1441 mmol) and benzene (300 mL). The mixture was refluxed andwater was removed by a Dean-Stark trap. 130 mL of water was removed over3 h. After cooling under nitrogen, the benzene solution was transferredto a clean 1 L flask with 4 Å mol. sieves and diluted with anhydrousCH₂Cl₂ (300 mL) to obtain a 14.6 weight % solution of2,2-dimethoxyacetaldehyde. ¹H NMR (400 MHz, CDCl₃) δ 9.49 (d, J=1.3 Hz,1H), 4.50 (d, J=1.5 Hz, 1H), 3.48 (s, 6H).(R)-4-Benzyl-3-propionyloxazolidin-2-one (10.0 g, 42.9 mmol) wasdissolved in anhydrous CH₂Cl₂ (50.0 mL) in a dry 3-neck 500 mL flask.The solution was cooled to below −20° C. A 1 M solution of TiCl₄ inCH₂Cl₂ (45.0 mL, 45.0 mmol) was added slowly. After the addition, thereaction mixture was warmed to 0° C. Once the internal temperaturereached 0° C., the reaction mixture was recooled to −20° C. TMEDA (9.70mL, 64.3 mmol) was added slowly. DIPEA (7.49 mL, 42.9 mmol) was addedslowly. The reaction mixture was warmed to 0° C. for 5-10 min. The darkred solution was recooled to below −40° C. A cold 14.6 weight % solutionof 2,2-dimethoxyacetaldehyde (45.6 mL, 72.9 mmol) was added via additionfunnel as a stream. After the addition, the internal temperature wasraised to 0° C. and then carefully to 15° C. The reaction mixture wasrecooled to −20° C. and quenched with sat. aq. NH₄Cl (150 mL) and thenstirred at rt for 30 min. Most of the clear CH₂Cl₂ phase separated out.The remaining solution with yellow sticky precipitates was filteredthough a CELITE® pad. The filtrate was extracted with CH₂Cl₂. The CH₂Cl₂phases were combined, washed with sat. aq. NH₄Cl (2×50 mL) and brine,dried (MgSO₄), and concentrated. Hexane (400 mL) was added and thereaction mixture was stirred for 30 min. The product crystallized out.The solid was filtered and then dissolved in a minimal amount of CH₂Cl₂(˜30 mL). Hexane (400 mL) was added while stirring to recrystallize theproduct. The solid was filtered to obtain 1Z (10.5 g, 31.1 mmol, 73%yield) as a white solid. LC-MS Anal. Calc'd for C₁₇H₂₃NO₆: 337.37, found[M-MeOH+H] 306.1. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 2H), 7.30-7.27(m, 1H), 7.23-7.18 (m, 2H), 4.74-4.63 (m, 1H), 4.33 (d, J=6.0 Hz, 1H),4.23-4.14 (m, 2H), 4.07-3.95 (m, 2H), 3.42 (s, 3H), 3.38 (s, 3H), 3.27(dd, J=13.4, 3.1 Hz, 1H), 2.78 (dd, J=13.3, 9.5 Hz, 1H), 2.55 (d, J=3.5Hz, 1H), 1.32 (d, J=6.8 Hz, 3H).

1AA. (2R,3R)-3-Hydroxy-N,4,4-trimethoxy-N,2-dimethylbutanamide

To a suspension of N,O-dimethylhydroxylamine hydrochloride (147 g, 1510mmol) in THF (750 mL) at −40° C. was added a 2 M solution oftrimethylaluminum in toluene (756 mL, 1510 mmol). After the addition,the reaction mixture was cooled to −78° C. and a solution of 1Z (170 g,504 mmol) in THF (750 mL) was added. The reaction mixture was warmed to0° C. and stirred for 1 h. To a 5 L beaker with sat. aq. Rochelle's saltcooled by dry ice was added the reaction mixture in portions. Afterstirring for 15 min, sat. aq. NH₄Cl was added. The mixture was dilutedwith CH₂Cl₂ and the layers were separated. The aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated. The crude product waspurified by chiral SFC (Column: Luxcellulose-2 (250×30 mm, 5 μM); 70%CO₂, Mobile phase: 0.25% DEA in MeOH; Total flow: 100 g/min; backpressure: 100 bar; 25° C.; Sample prep: 173 mg/mL). The product wascollected and concentrated to provide 1AA (85 g, 38 mmol, 75% yield).LC-MS Anal. Calc'd for C₉H₁₉NO₅: 221.25, found [M-MeOH+H] 190.1. ¹H NMR(300 MHz, CDCl₃) δ 4.31 (d, J=6.0 Hz, 1H), 3.94-3.85 (m, 1H), 3.70 (s,3H), 3.43 (s, 3H), 3.40 (s, 3H), 3.23 (d, J=2.6 Hz, 1H), 3.18 (s, 3H),3.15-3.04 (m, 1H), 1.22 (d, J=6.8 Hz, 3H).

1BB.(2R,3R)—N,4,4-Trimethoxy-3-(3-methoxypropoxy)-N,2-dimethylbutanamide

To a 5 L round bottom flask was added 1AA (104 g, 470 mmol), THF (800mL), 3-methoxypropyl methanesulfonate (158 g, 940 mmol), THF (200 mL),and a 1 M solution of TBAF in THF (705 mL, 705 mmol). The solution wascooled to 0° C. and then 60% NaH (75.0 g, 1800 mmol) was addedportionwise. After the addition was complete, the reaction mixture wasstirred for 1 h, holding the temperature below 20° C. The mixture waspoured into 5 L beaker containing ice/water. Sat. aq. NH₄Cl was addeduntil the pH ˜8. The product was extracted with EtOAc and CH₂Cl₂ (3×250mL). The combined organic layers were dried over Na₂SO₄ andconcentrated. The crude product was purified by silica chromatography togive 1BB (125 g, 426 mmol, 91% yield) as a red oil. LC-MS Anal. Calc'dfor C₁₃H₂₇NO₆: 293.36, found [M-MeOH+H]262.1. ¹H NMR (400 MHz, CDCl₃) δ4.24 (d, J=4.8 Hz, 1H), 3.82 (dt, J=9.1, 6.2 Hz, 1H), 3.68 (s, 3H),3.66-3.56 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 3.40 (s, 3H), 3.38 (s, 3H),3.32 (s, 3H), 3.17 (s, 3H), 3.15-3.07 (m, 1H), 1.92-1.75 (m, 2H), 1.20(d, J=7.0 Hz, 3H).

1CC. (2R,3R)-4,4-Dimethoxy-3-(3-methoxypropoxy)-2-methylbutanal

To a solution of 1BB (240 g, 818 mmol) in THF (2500 mL) was added a 1 Msolution of DIBAL-H in THF (1227 mL, 1227 mmol) over 10 min at −78° C.The reaction mixture was stirred for 2 h. A 0° C. solution of sat. aq.Rochelle's salt was added to the reaction mixture. The reaction mixturewas extracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated to provide 1CC (170 g, 726mmol, 89% yield), which was used without further purification. ¹H NMR(400 MHz, CDCl₃) δ 9.78-9.51 (m, 1H), 4.29 (d, J=5.9 Hz, 1H), 3.81-3.75(m, 1H), 3.72 (dd, J=6.1, 4.7 Hz, 1H), 3.55-3.48 (m, 2H), 3.46 (s, 3H),3.40 (s, 3H), 3.41 (t, J=6.3 Hz, 1H), 3.31 (s, 3H), 2.67-2.57 (m, 1H),1.84-1.74 (m, 2H), 1.14 (d, J=7.0 Hz, 3H). 1DD.(3S,4R)-1,1-Dibromo-5,5-dimethoxy-4-(3-methoxypropoxy)-3-methylpent-1-ene:To a solution of CBr₄ (299 g, 901 mmol) in CH₂Cl₂ (2000 mL) at 0° C. wasadded Ph₃P (472 g, 1800 mmol) in portions. The solution was stirred at0° C. for 10 min and then a solution of 1CC (176 g, 751 mmol) in CH₂Cl₂(1000 mL) was added dropwise. The reaction mixture was vigorouslystirred at 0° C. for 1 h. The excess dibromophosphorane was quenched bythe sequential addition of Et₃N (253 mL, 1800 mmol) followed by MeOH (76mL, 1900 mmol) and the solution was stirred at rt. The solution was thenadded to a solution of 5:1 hexane:Et₂O (1800 mL), resulting in theprecipitation of the triphenylphosphine oxide. The light brown solid wasremoved by filtration and washed with hexane (750 mL). The filtrate wasevaporated and purified by silica chromatography to give 1DD (212 g, 543mmol, 72% yield) as a red oil. ¹H NMR (400 MHz, CDCl₃) δ 6.39 (d, J=9.7Hz, 1H), 4.22 (d, J=6.4 Hz, 1H), 3.82 (dt, J=9.2, 5.9 Hz, 1H), 3.45 (s,3H), 3.55-3.43 (m, 3H), 3.39 (s, 3H), 3.34 (s, 3H), 3.22 (dd, J=6.4, 4.2Hz, 1H), 2.75 (dqd, J=9.6, 6.8, 4.2 Hz, 1H), 1.89-1.75 (m, 2H), 1.03 (d,J=6.8 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 141.5, 105.6, 87.7, 81.0,69.5, 69.5, 58.6, 55.7, 54.1, 39.8, 30.4, 13.2.

1EE. (4S,5R)-Ethyl6,6-dimethoxy-5-(3-methoxypropoxy)-4-methylhex-2-ynoate

To a solution of 1DD (212 g, 543 mmol) in THF (2000 mL) at −78° C. wasadded a solution of 2.5 M solution of n-BuLi in hexanes (456 mL, 1141mmol). The reaction mixture was stirred at −78° C. for 30 min and thenethyl chloroformate (110 mL, 1140 mmol) was added. The reaction mixturewas warmed to rt and stirred for 1 h. The reaction mixture was quenchedwith sat. aq. NH₄Cl and extracted with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated. Thecrude product was purified by silica chromatography to provide 1EE (142g, 446 mmol, 82% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ4.31 (d, J=5.5 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.86-3.76 (m, 1H), 3.69(dt, J=9.4, 6.3 Hz, 1H), 3.46 (s, 3H), 3.49-3.43 (m, 2H), 3.39 (s, 3H),3.41-3.37 (m, 1H), 3.31 (s, 3H), 2.88 (qd, J=7.0, 4.6 Hz, 1H), 1.89-1.79(m, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.23 (d, J=7.0 Hz, 3H). ¹³C NMR (126MHz, CDCl₃) δ 153.7, 105.2, 91.0, 81.2, 73.8, 69.8, 69.6, 61.7, 58.5,55.9, 55.0, 30.3, 27.7, 14.6, 14.0.

1FF. (4S,5R,Z)-Ethyl6,6-dimethoxy-5-(3-methoxypropoxy)-4-methylhex-2-enoate

To a solution of 1EE (53.0 g, 175 mmol) in THF (500 mL) and pyridine(42.5 mL, 526 mmol) was added Lindlar Catalyst (44.8 g, 21.0 mmol). Thereaction mixture was degassed and stirred at rt under H₂ (1 atm) for 8h. The reaction mixture was filtered though CELITE® and concentrated.The crude material was purified by silica chromatography to provide 1FF(45.5 g, 148 mmol, 84% yield) as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 6.18 (dd, J=11.7, 10.2 Hz, 1H), 5.71 (dd, J=11.7, 1.1 Hz, 1H),4.24 (d, J=6.8 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.84-3.69 (m, 2H),3.52-3.44 (m, 3H), 3.43 (s, 3H), 3.37 (s, 3H), 3.32 (s, 3H), 3.22 (dd,J=6.8, 4.2 Hz, 1H), 1.86-1.75 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.03 (d,J=6.8 Hz, 3H). ¹³C NMR (101 MHz, CHLOROFORM-d) δ 166.2, 152.6, 118.3,105.9, 82.1, 77.2, 69.7, 69.5, 59.8, 58.5, 55.5, 53.9, 34.3, 30.5, 14.2.

1GG. (4S,5R,Z)-Ethyl 5-(3-methoxypropoxy)-4-methyl-6-oxohex-2-enoate

To a solution of 1FF (9.91 g, 32.6 mmol) in THF (65 mL) was added 1 Naq. HCl (67.8 mL, 67.8 mmol). The reaction mixture was heated to 50° C.overnight. The reaction mixture was cooled to rt and diluted with EtOAc.The layers were separated. The aqueous layer was extracted with EtOAc.The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated to give 1GG (8.41 g, 32.6 mmol, 100% yield) as a colorlessoil, which was used without further purification. LC-MS Anal. Calc'd forC₁₃H₂₂O₅: 258.31, found [M+H] 259.0. ¹H NMR (500 MHz, CDCl₃) δ 9.64 (d,J=1.9 Hz, 1H), 6.12 (dd, J=11.4, 10.0 Hz, 1H), 5.80 (dd, J=11.4, 1.0 Hz,1H), 4.17 (q, J=7.0 Hz, 2H), 4.05-3.92 (m, 1H), 3.69 (dt, J=9.3, 6.1 Hz,1H), 3.58 (dd, J=5.6, 2.1 Hz, 1H), 3.54-3.44 (m, 3H), 3.33 (s, 3H),1.92-1.82 (m, 2H), 1.29 (t, J=7.2 Hz, 3H), 1.08 (d, J=6.9 Hz, 3H). ¹³CNMR (101 MHz, CDCl₃) δ 202.9, 165.9, 149.6, 120.3, 87.4, 69.3, 68.3,60.1, 58.6, 34.0, 30.1, 15.1, 14.2.

1HH. Ethyl2-((2S,3S,4R)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetate

To a solution of NaBH(OAc)₃ (11.0 g, 51.9 mmol) and 1× (12.0 g, 34.6mmol) in CH₂Cl₂ (176 mL) vigorously stirring at rt was added a solutionof 1GG (9.11 g, 35.3 mmol) in CH₂Cl₂ (88 mL) dropwise over 50 min. Thereaction mixture was stirred at rt for 20 min. The reaction mixture wascooled to 0° C. and 1.5 M aq. K₂HPO₄ (150 mL) was added dropwise viaaddition funnel. The reaction mixture was stirred at rt for 15 min andextracted with CH₂Cl₂ (3×). The combined CH₂Cl₂ extracts were washedwith brine, dried (MgSO₄), and concentrated to give the resulting crudeproduct (4S,5R,Z)-ethyl6-((4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)amino)-5-(3-methoxypropoxy)-4-methylhex-2-enoateas a dark brown oil, which was used directly in the next step. To asolution of (4S,5R,Z)-ethyl6-((4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)amino)-5-(3-methoxypropoxy)-4-methylhex-2-enoatein THF (346 mL) at rt was added NaOtBu (3.66 g, 38.0 mmol) in severalportions. After the addition, the reaction mixture was stirred at rt for5 min. The reaction mixture was quenched with sat. aq. NH₄Cl. Theproduct was extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated. The crude productwas purified by silica chromatography to afford ethyl2-((2S,3S,4R)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetate(14.9 g, 25.2 mmol, 73% yield) as a yellow oil. 137 g (232 mmol) of thematerial was further purified by chiral SFC (Lux Cellulose-4 column(3×25 cm, 5 μM); 100 bars; 50° C.; 160 mL/min; Mobile Phase: CO₂/MeOH(67/33); Detector Wavelength: 220 nM; Separation Program: sequenceinjection; Injection: 3.0 mL with cycle time 4.55 min; Samplepreparation: 137 g/900 mL 3:1 MeOH:CH₂Cl₂ (15.2 mg/mL)) to provide ethyl2-((2S,3S,4R)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetate(120 g, 203 mmol, 88% yield) as a light orange oil. The material wasrepurified by silica chromatography to obtain quantitative yield of 1HH(120 g) as a light yellow oil. LC-MS Anal. Calc'd for C₃₁H₄₄ClN₃O₆:589.29, found [M+H] 590.1. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (s, 1H), 6.88(d, J=9.0 Hz, 2H), 6.51 (d, J=9.0 Hz, 2H), 6.26 (s, 1H), 4.17 (q, J=7.2Hz, 2H), 3.88 (s, 3H), 3.80-3.73 (m, 2H), 3.72-3.68 (m, 1H), 3.61-3.55(m, 1H), 3.55-3.48 (m, 3H), 3.48-3.39 (m, 4H), 3.36-3.28 (m, 3H),2.86-2.73 (m, 2H), 2.73-2.55 (m, 2H), 2.36 (q, J=7.1 Hz, 1H), 2.21-2.05(m, 2H), 1.88-1.73 (m, 3H), 1.28 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.6 Hz,3H), 1.00 (d, J=7.3 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 172.6, 164.1,157.6, 148.8, 146.6, 141.8, 118.8, 118.2, 112.5, 100.4, 84.7, 80.9,69.6, 65.9, 62.3, 60.3, 58.6, 55.0, 53.6, 52.9, 48.3, 43.3, 37.2, 36.1,30.1, 29.8, 18.6, 15.7, 14.3.

Example 1

To a stirred solution of 1HH (21.5 g, 36.4 mmol) in degassed THF (260mL), IPA (52 mL), and water (52 mL) at 0° C. was added 1 M aq. LiOH (109mL, 109 mmol) dropwise. The reaction mixture was warmed to rt slowly andstirred for 16 h. The reaction mixture was partitioned between water(500 mL) and hexane (600 mL) and the layers were separated. The aqueouslayer was cooled to 0° C. and then acidified by addition of 1 M aq. HCldropwise until pH ˜4-5 with stirring. The product was extracted withCH₂Cl₂ (3×250 mL). The combined organic extracts were dried (MgSO₄),concentrated by rotary evaporation at rt, and then dried under highvacuum for 16 h while protecting from light to afford Example 1 (20.5 g,36.5 mmol, 100% yield) as an off-white foam. LC-MS Anal. Calc'd forC₂₉H₄₀ClN₃O₆: 561.26, found [M+H] 562.2. ¹H NMR (400 MHz, CDCl₃) δ 7.97(s, 1H), 6.90 (d, J=9.0 Hz, 2H), 6.58 (d, J=9.0 Hz, 2H), 6.26 (s, 1H),3.88 (s, 3H), 3.79 (td, J=8.7, 4.0 Hz, 1H), 3.76-3.69 (m, 2H), 3.63-3.41(m, 8H), 3.34 (s, 3H), 2.89-2.70 (m, 3H), 2.62 (dd, J=12.1, 9.2 Hz, 1H),2.40 (q, J=7.1 Hz, 1H), 2.22-2.06 (m, 2H), 1.89-1.75 (m, 3H), 1.14 (d,J=6.8 Hz, 3H), 1.04 (d, J=7.3 Hz, 3H). ¹³C NMR (126 MHz, DMSO-d₆) δ173.2, 163.7, 157.2, 148.4, 146.3, 141.6, 118.3, 117.2, 112.3, 100.3,83.8, 79.7, 68.9, 65.3, 62.2, 57.8, 54.2, 53.3, 52.6, 47.8, 42.8, 37.0,36.0, 29.7, 29.6, 18.4, 15.3.

Example 1, MSA Salt

Example 1 (28.8 g, 51.2 mmol) was dissolved in CH₃CN (256 mL). Thesolution was cooled to 0° C. and MSA (4.92 g, 51.2 mmol) was addeddropwise. After the addition, the solution was concentrated. Theresulting residue was dissolved in CH₂Cl₂ (60 mL) and hexanes was addeddropwise (˜240 mL). A gummy solid was formed and the solution wasdecanted. The gummy solid was concentrated and dried under high vacuumwith protection from light to obtain Example 1, MSA salt (33.0 g, 50.1mmol, 98% yield) as a light beige solid. LC-MS Anal. Calc'd forC₂₉H₄₀ClN₃O₆: 561.26, found [M+H] 562.2. ¹H NMR (500 MHz, CH₃CN-d₃) δ8.04 (s, 1H), 7.17 (br d, J=8.0 Hz, 2H), 7.01 (d, J=9.1 Hz, 2H), 6.40(s, 1H), 4.13-4.06 (m, 1H), 3.94 (s, 3H), 3.92-3.87 (m, 1H), 3.82-3.75(m, 1H), 3.75-3.66 (m, 3H), 3.66-3.60 (m, 1H), 3.53 (td, J=6.4, 1.2 Hz,2H), 3.43 (t, J=6.3 Hz, 2H), 3.27 (s, 3H), 3.10 (ddd, J=13.0, 10.5, 2.9Hz, 1H), 2.88 (dd, J=12.9, 9.6 Hz, 1H), 2.82-2.74 (m, 1H), 2.73-2.65 (m,1H), 2.63 (s, 3H), 2.38-2.31 (m, 1H), 2.25-2.16 (m, 1H), 2.11-2.01 (m,1H), 1.78 (quin, J=6.3 Hz, 2H), 1.75-1.66 (m, 1H), 1.13 (d, J=7.2 Hz,3H), 1.08 (d, J=6.9 Hz, 3H). ¹³C NMR (126 MHz, 120° C., DMSO-d₆) δ172.1, 163.4, 156.8, 148.9, 145.6, 140.8, 135.6, 117.9, 116.5, 113.0,99.4, 83.4, 79.5, 68.6, 65.3, 62.4, 57.2, 53.7, 53.0, 52.9, 47.2, 43.0,36.4, 35.5, 29.3, 29.2, 17.5, 14.6.

Example 22-((2S,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid, HCl

2A.5-Chloro-4-((3,4-trans)-4-((5-iodopyridin-2-yl)oxy)-3-methylpiperidin-1-yl)-2-methoxypyridine

To a solution of 1P, Isomer 1 (494 mg, 1.92 mmol) and 5-iodopyridin-2-ol(340 mg, 1.54 mmol) in toluene (8 mL) was added Bu₃P (0.58 mL, 2.3mmol). ADDP (582 mg, 2.31 mmol) was added in three portions to thereaction mixture over 11 min and the reaction mixture became a thickslurry. The reaction mixture was sonicated for 1 h, stirred at 60° C.for 2 h, and then stirred at rt for 16 h. The reaction mixture wastreated with hexanes (50 mL). After stirring for 5 min, the mixture wasfiltered and concentrated. The residue was purified by silicachromatography to provide 2A (534 mg, 1.05 mmol, 68% yield) as a whitesolid. LC-MS Anal. Calc'd for C₁₇H₁₉ClIN₃O₂: 459.71, found [M+H] 460.1,461.9. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (dd, J=2.4, 0.7 Hz, 1H), 7.96 (s,1H), 7.77 (dd, J=8.8, 2.4 Hz, 1H), 6.58 (dd, J=8.7, 0.6 Hz, 1H), 6.26(s, 1H), 4.82 (td, J=9.3, 4.3 Hz, 1H), 3.88 (s, 3H), 3.60-3.46 (m, 2H),2.99-2.84 (m, 1H), 2.61 (dd, J=12.3, 9.7 Hz, 1H), 2.33-2.22 (m, 1H),2.20-2.07 (m, 1H), 1.84-1.73 (m, 1H), 1.02 (d, J=6.6 Hz, 3H).

2B.2-((2S,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetonitrile

2B was prepared from 2A following the procedure of Example 1. LC-MSAnal. Calc'd for C₂₈H₃₈ClN₅O₄: 544.09, found [M+] 544.2. ¹H NMR (400MHz, CDCl₃) δ 7.97 (s, 1H), 7.47 (d, J=2.9 Hz, 1H), 6.94 (dd, J=9.0, 3.1Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 4.73 (td, J=9.3, 4.3 Hz,1H), 3.89 (s, 3H), 3.77 (d, J=2.0 Hz, 1H), 3.65 (dd, J=9.1, 3.6 Hz, 1H),3.62-3.50 (m, 4H), 3.49-3.40 (m, 4H), 3.33 (s, 3H), 2.99-2.88 (m, 1H),2.87-2.77 (m, 1H), 2.76-2.67 (m, 1H), 2.66-2.51 (m, 2H), 2.35-2.24 (m,1H), 2.20-2.07 (m, 1H), 1.89-1.71 (m, 3H), 1.06 (d, J=3.5 Hz, 3H), 1.04(d, J=2.9 Hz, 3H).

Example 2

To a solution of 2B (33 mg, 0.061 mmol) in EtOH (0.5 mL) was added 6 Maq. KOH (0.20 mL, 1.2 mmol). The reaction mixture was heated in a sealedmicrowave vial to 125° C. for 5 h and then cooled to rt. The reactionmixture was concentrated, acidified with 1 N aq. HCl, and extracted withCH₂Cl₂. The combined organic layers were washed with water and brine,dried (Na₂SO₄), and concentrated. The crude product was purified byRP-Prep. HPLC and the fractions containing product were lyophilized. Theproduct was treated with CH₃CN (0.5 mL) and 3 N aq. HCl (0.5 mL) andconcentrated. The procedure was repeated (2×) to yield Example 2 (11 mg,0.018 mmol, 29% yield) as a green powder. LC-MS Anal. Calc'd forC₂₈H₃₉ClN₄O₆: 562.2, found [M+H] 563.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.03(s, 1H), 7.55-7.35 (m, 1H), 7.25-7.04 (m, 1H), 6.95-6.76 (m, 1H), 6.43(s, 1H), 4.73-4.61 (m, 1H), 3.82 (s, 3H), 3.79-3.71 (m, 1H), 3.66-3.57(m, 1H), 3.55-3.30 (m, 8H), 3.21 (s, 3H), 2.99-2.84 (m, 1H), 2.74-2.64(m, 1H), 2.63-2.53 (m, 2H), 2.39-2.24 (m, 1H), 2.22-2.12 (m, 1H),2.04-1.86 (m, 1H), 1.73 (s, 2H), 1.67-1.50 (m, 1H), 0.96 (dd, J=17.3,6.9 Hz, 6H). Analytical HPLC: RT=8.15 min, HI: 95.7%. hGPR40 EC₅₀=180nM. hGPR40 IP1 EC₅₀=27 nM.

Example 32-((2S,3S,4R)-1-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid, HCl

3A. 1-(5-Ethoxy-2-fluorophenyl)piperidin-4-ol

A mixture of 4-ethoxy-1,2-difluorobenzene (17.5 mL, 126 mmol),piperidin-4-ol (39.2 g, 379 mmol), DMSO (42 mL), and pyridine (21.1 mL)in a flask equipped with a reflux condenser under nitrogen was heated to140° C. for 48 h. The reaction mixture was cooled to rt, diluted with4/1 hexanes/EtOAc, and washed with 2% aq. NaHCO₃, water, and brine. Theorganic layer was dried (MgSO₄) and concentrated. The crude product waspurified by silica chromatography to provide 3A (10.6 g, 44.2 mmol, 35%yield) as a yellow oil. LC-MS Anal. Calc'd for C₁₃H₁₈FNO₂: 239.29, found[M+H] 240.1. ¹H NMR (400 MHz, CDCl₃) δ 6.90 (dd, J=12.3, 8.8 Hz, 1H),6.51 (dd, J=7.4, 3.0 Hz, 1H), 6.39 (dt, J=8.8, 3.2 Hz, 1H), 3.97 (q,J=7.0 Hz, 2H), 3.89-3.78 (m, 1H), 3.41-3.30 (m, 2H), 2.82 (ddd, J=12.2,9.5, 3.0 Hz, 2H), 2.04-1.95 (m, 2H), 1.74 (dtd, J=12.9, 9.2, 3.7 Hz,2H), 1.53-1.46 (m, 1H), 1.39 (t, J=6.9 Hz, 3H).

3B. 1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl 4-methylbenzenesulfonate

To a solution of 3A (10.4 g, 43.4 mmol) and 4-methylbenzene-1-sulfonylchloride (12.4 g, 65.1 mmol) in CH₂Cl₂ (108 mL), was added pyridine(35.1 mL, 434 mmol) dropwise. The reaction mixture was stirred at rtovernight. The reaction mixture was diluted with EtOAc, washed withwater and brine, dried (MgSO₄), and concentrated. The crude product waspurified by silica chromatography to provide 3B (13.4 g, 34.1 mmol, 79%yield) as a colorless oil. LC-MS Anal. Calc'd for C₂₀H₂₄FNO₄S: 393.47,found [M+H]394.1. ¹H NMR (400 MHz, CDCl₃) δ 7.86-7.78 (m, 2H), 7.39-7.31(m, 2H), 6.88 (dd, J=12.1, 8.8 Hz, 1H), 6.46 (dd, J=7.4, 3.0 Hz, 1H),6.39 (dt, J=8.9, 3.2 Hz, 1H), 4.69 (tt, J=7.4, 3.8 Hz, 1H), 3.96 (q,J=6.9 Hz, 2H), 3.22 (ddd, J=11.8, 7.3, 4.0 Hz, 2H), 2.90 (ddd, J=11.8,7.6, 3.9 Hz, 2H), 2.46 (s, 3H), 2.03-1.86 (m, 4H), 1.38 (t, J=6.9 Hz,3H).

3C. 1-(5-Ethoxy-2-fluorophenyl)-4-(4-iodophenoxy)piperidine

A solution of 4-iodophenol (5.62 g, 25.6 mmol), 3B (6.704 g, 17.04mmol), and Cs₂CO₃ (16.7 g, 51.1 mmol) in anhydrous DMF (43 mL) washeated to 55° C. for 16 h. The reaction mixture was diluted with EtOAcand water and extracted with EtOAc (3×). The combined organic layerswere washed with water, dried (MgSO₄), and concentrated. The crudeproduct was purified by silica chromatography to provide 3C (3.99 g,9.04 mmol, 53% yield) as a white solid. LC-MS Anal. Calc'd forC₁₉H₂₁FINO₂: 441.28, found [M+H]442.0. ¹H NMR (400 MHz, CDCl₃) δ7.61-7.51 (m, 2H), 6.91 (dd, J=12.1, 8.8 Hz, 1H), 6.76-6.67 (m, 2H),6.53 (dd, J=7.4, 3.0 Hz, 1H), 6.40 (dt, J=8.8, 3.2 Hz, 1H), 4.42 (tt,J=7.2, 3.6 Hz, 1H), 3.98 (q, J=6.9 Hz, 2H), 3.31 (ddd, J=11.6, 7.8, 3.5Hz, 2H), 2.98 (ddd, J=11.8, 8.0, 3.5 Hz, 2H), 2.17-2.05 (m, 2H),2.02-1.90 (m, 2H), 1.39 (t, J=6.9 Hz, 3H).

Example 3 (green powder, 13 mg) was prepared from 3C following theprocedure of Example 1. LC-MS Anal. Calc'd for C₃₀H₄₁FN₂O₆: 544.3, found[M+H] 545.3. ¹H NMR (400 MHz, DMSO-d₆) δ 7.01 (dd, J=12.5, 8.8 Hz, 1H),6.90 (d, J=8.8 Hz, 2H), 6.60-6.42 (m, 4H), 4.30 (br. s., 1H), 3.97 (q,J=7.0 Hz, 2H), 3.74 (d, J=4.0 Hz, 1H), 3.62 (d, J=9.5 Hz, 1H), 3.54-3.40(m, 3H), 3.37 (t, J=6.3 Hz, 2H), 3.30-3.22 (m, 2H), 3.21 (s, 3H), 2.90(t, J=8.8 Hz, 2H), 2.70-2.57 (m, 1H), 2.27 (d, J=7.0 Hz, 1H), 2.27-2.20(m, 1H), 2.27-2.20 (m, 1H), 2.07-1.93 (m, 2H), 1.80-1.66 (m, 4H), 1.30(t, J=6.9 Hz, 3H), 0.95 (d, J=7.0 Hz, 3H). Analytical HPLC: RT=10.0 min,HI: 94.8%. hGPR40 EC₅₀=200 nM.

Example 42-((2S,3S,4R)-1-(4-((1-(5-Chloro-2-methoxypyridin-4-yl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

4A. 1-(5-Chloro-2-methoxypyridin-4-yl)piperidin-4-ol

A solution of 1J (2.80 g, 12.6 mmol), piperidin-4-ol (1.40 g, 13.8mmol), and K₂CO₃ (8.70 g, 62.9 mmol) in DMSO (30 mL) was stirred at 110°C. for 14 h. The reaction mixture was partitioned between water (150 mL)and EtOAc (150 mL). The organic layer was separated, washed with water(2×100 mL) and brine (100 mL), dried over MgSO₄, filtered, andconcentrated. The residue was purified by silica chromatography to give4A (2.70 g, 11.1 mmol, 88% yield) as a colorless oil. LC-MS Anal. Calc'dfor C₁₁H₁₅ClN₂O₂: 242.70 found [M+H] 243.0. ¹H NMR (400 MHz, CDCl₃) δ7.97 (s, 1H), 6.27 (s, 1H), 3.94-3.84 (m, 4H), 3.51-3.37 (m, 2H), 2.90(ddd, J=12.3, 9.2, 3.0 Hz, 2H), 2.07-1.95 (m, 2H), 1.84-1.66 (m, 2H).

Example 4 (white powder, 28 mg) was prepared from 4A following theprocedure of Example 1. LC-MS Anal. Calc'd for C₂₈H₃₈ClN₃O₆: 547.2,found [M+H] 548.2. ¹H NMR (400 MHz, CD₃CN) δ 7.96 (s, 1H), 6.87 (d,J=9.0 Hz, 2H), 6.54 (d, J=9.0 Hz, 2H), 6.35 (s, 1H), 4.48-4.14 (m, 1H),3.82 (s, 3H), 3.75-3.70 (m, 1H), 3.68-3.61 (m, 1H), 3.57-3.43 (m, 2H),3.40 (t, J=6.3 Hz, 4H), 3.24 (s, 3H), 3.07-2.90 (m, 2H), 2.73-2.51 (m,2H), 2.37-2.24 (m, 1H), 2.20-1.98 (m, 4H), 1.76 (t, J=6.3 Hz, 4H), 0.96(d, J=7.3 Hz, 3H). Analytical HPLC: RT=9.26 min, HI: 98.2%. hGPR40EC₅₀=73 nM. hGPR40 IP1 EC₅₀=13 nM.

Example 52-((2S,3S,4R)-1-(6-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 5 (beige solid, 59 mg) was prepared from 3A and5-iodopyridin-2-ol following the procedure of Example 2. LC-MS Anal.Calc'd for C₂₉H₄₀FN₃O₆: 545.64, found [M+H] 546.3. ¹H NMR (400 MHz,CD₃CN) δ 7.48 (d, J=3.1 Hz, 1H), 7.04 (dd, J=8.9, 3.2 Hz, 1H), 6.93 (dd,J=12.4, 8.9 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.54 (dd, J=7.4, 3.0 Hz,1H), 6.42 (dt, J=8.9, 3.2 Hz, 1H), 4.97 (tt, J=8.2, 4.0 Hz, 1H), 3.97(q, J=6.9 Hz, 2H), 3.77-3.72 (m, 1H), 3.71-3.64 (m, 1H), 3.57-3.44 (m,2H), 3.43-3.35 (m, 4H), 3.34-3.26 (m, 2H), 3.25 (s, 3H), 2.92 (ddd,J=12.0, 9.1, 3.1 Hz, 2H), 2.75-2.58 (m, 2H), 2.34 (q, J=7.1 Hz, 1H),2.15-2.02 (m, 2H), 1.88-1.70 (m, 4H), 1.32 (t, J=7.0 Hz, 3H), 0.97 (d,J=7.3 Hz, 3H). Analytical HPLC: RT=8.1 min, HI: 99.1%. hGPR40 EC₅₀=170nM.

Example 62-((2S,3S,4R)-1-(6-((1-(5-Chloro-2-methoxypyridin-4-yl)piperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 6 was prepared from 4A and 5-iodopyridin-2-ol following theprocedure of Example 2 to yield Example 6 (white solid, 21 mg). LC-MSAnal. Calc'd for C₂₇H₃₇ClN₄O₆: 549.06, found [M+H] 549.2. ¹H NMR (400MHz, CD₃CN) δ 7.96 (s, 1H), 7.48 (d, J=3.1 Hz, 1H), 7.04 (dd, J=9.0, 3.1Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.35 (s, 1H), 5.04 (tt, J=7.8, 3.9 Hz,1H), 3.83 (s, 3H), 3.75 (dt, J=4.6, 1.7 Hz, 1H), 3.68 (ddd, J=9.1, 4.0,1.2 Hz, 1H), 3.58-3.46 (m, 2H), 3.46-3.34 (m, 6H), 3.25 (s, 3H), 3.04(ddd, J=12.2, 8.7, 3.1 Hz, 2H), 2.75-2.59 (m, 2H), 2.34 (q, J=7.3 Hz,1H), 2.15-2.04 (m, 2H), 1.89-1.80 (m, 2H), 1.77 (quin, J=6.3 Hz, 2H),0.97 (d, J=7.3 Hz, 3H). Analytical HPLC: RT=7.2 min, HI: 97.9%. hGPR40EC₅₀=200 nM. hGPR40 IP1 EC₅₀=19 nM.

Example 72-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-3-fluorophenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 7 (yellow oil, 31.9 mg) was prepared as a single isomer from2-fluoro-4-iodophenol and 1P, Isomer 1 following the procedure ofExample 1. LC-MS Anal. Calc'd for C₂₉H₃₉ClFN₃O₆: 579.2, found [M+H]580.3. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.94 (s, 1H), 6.96 (t, J=9.1 Hz, 1H),6.36 (dd, J=14.0, 2.8 Hz, 1H), 6.30 (d, J=2.6 Hz, 1H), 6.28 (s, 1H),3.85 (s, 3H), 3.78-3.65 (m, 3H), 3.64-3.36 (m, 8H), 3.30 (s, 3H),2.85-2.72 (m, 3H), 2.60 (dd, J=12.2, 9.6 Hz, 1H), 2.41 (q, J=7.0 Hz,1H), 2.16-2.03 (m, 2H), 1.88-1.73 (m, 3H), 1.16 (d, J=6.8 Hz, 3H), 1.00(d, J=7.3 Hz, 3H). Analytical HPLC (ZORBAX® method, 0% Solvent B start):RT=8.6 min, HI: 100%. hGPR40 EC₅₀=97 nM.

Example 82-((2S,3S,4R)-1-(4-((1-(5-Chloro-2-ethylpyridin-4-yl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid, HCl

8A. 8-(2-Chloropyridin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane

To a solution of 2-chloro-4-fluoropyridine (2.63 g, 20.0 mmol) and1,4-dioxa-8-azaspiro[4.5]decane (3.01 g, 21.0 mmol) in DMF (8 mL) wasadded NEt₃ (3.1 mL, 22 mmol). The reaction mixture was stirred at rt for40 h. The reaction mixture was diluted with EtOAc and the organic layerwas washed with brine, dried, and concentrated. The crude product waspurified by silica chromatography to provide 8A (4.78 g, 18.8 mmol, 94%yield). LC-MS Anal. Calc'd for C₁₂H₁₅ClN₂O₂: 254.08, found [M+H] 255.1.¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=6.1 Hz, 1H), 6.69 (d, J=2.5 Hz,1H), 6.6 (dd, J=6.1, 2.5 Hz, 1H), 4.02 (s, 4H), 3.52-3.50 (m, 4H),1.80-1.58 (m, 4H).

8B. 8-(2-Ethylpyridin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane

To a solution of 8A (1.90 g, 7.48 mmol) in dioxane (19 mL) was addedPdCl₂(dppf) (0.14 g, 0.19 mmol) and followed by a solution ofdiethylzinc (7.9 mL, 7.9 mmol) (1 M in hexane). The reaction mixture wasstirred at 70° C. for 1 h. The reaction mixture was quenched with sat.aq. NaHCO₃ and diluted with EtOAc. The layers were separated and theorganic layer was washed with water and brine, dried (MgSO₄), andconcentrated. Purification via silica chromatography yielded 8B (1.9 g,7.5 mmol, 100% yield). LC-MS Anal. Calc'd for C₁₄H₂₀N₂O₂: 248.15, found[M+H] 249.1. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (d, J=6.1 Hz, 1H), 6.56-6.51(m, 2H), 3.99 (s, 4H), 3.49-3.47 (m, 4H), 2.73-2.68 (m, 2H), 1.78-1.76(m, 4H), 1.28 (t, J=7.6, 7.6 Hz, 3H).

8C. 8-(5-Chloro-2-ethylpyridin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane

To a solution of 8B (150 mg, 0.60 mmol) in CH₃CN (2.3 mL) at rt wasadded K₂CO₃ (142 mg, 1.03 mmol) followed by NCS (137 mg, 1.03 mmol). Thereaction mixture was stirred at rt for 3.5 h. K₂CO₃ (25 mg, 0.18 mmol)and NCS (24.2 mg, 0.18 mmol) were added and the reaction mixture wasstirred at rt for 1 h. The reaction mixture was diluted with EtOAc,washed with sat. aq. NaHCO₃, water, and brine, dried (MgSO₄), andconcentrated. Purification via silica chromatography yielded 8C (52 mg,30% yield). LC-MS Anal. Calc'd for C₁₄H₁₉ClN₂O₂: 282.11, found [M+H]283.0. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 6.72 (s, 1H), 4.01 (s,4H), 3.29-3.27 (m, 4H), 2.76-2.71 (m, 2H), 1.90-1.88 (m, 4H), 1.29-1.26(m, 3H).

8D. 1-(5-Chloro-2-ethylpyridin-4-yl)piperidin-4-one

To a solution of 8C (68 mg, 0.24 mmol) in acetone (4.2 mL) and water(1.8 mL) was added TsOH (140 mg, 0.72 mmol). The reaction mixture washeated to 60° C. for 19 h and concentrated. The reaction mixture wastreated with solid NaHCO₃ and diluted with EtOAc. The organic layer waswashed with sat. aq. NaHCO₃, water, and brine, dried (MgSO₄), andconcentrated. Purification via silica chromatography yielded 8D (37.4mg, 0.157 mmol, 65% yield). LC-MS Anal. Calc'd for C₁₂H₁₅ClN₂O: 238.09,found [M+H] 239.1. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 6.74 (s, 1H),3.51-3.48 (m, 4H), 2.78-2.73 (m, 2H), 2.66-2.64 (m, 4H), 1.31-1.27 (m,3H).

8E. 1-(5-Chloro-2-ethylpyridin-4-yl)piperidin-4-ol

To a solution of 8D (37 mg, 0.16 mmol) in MeOH (1 mL) and THF (0.6 mL)at 0° C., NaBH₄ (18 mg, 0.47 mmol) was added in portions. The reactionmixture was stirred at 0° C. for 30 min and at rt for 10 min. Thereaction mixture was cooled to 0° C. and quenched with sat. aq. NaHCO₃(2 mL). The MeOH and THF were evaporated. The residue was extracted withEtOAc. The combined extracts were washed with water and brine, dried(MgSO₄), and concentrated to give 8E as a gum, (38 mg, 0.16 mmol, 100%yield), which was used without further purification. LC-MS Anal. Calc'dfor C₁₂H₁₇ClN₂O: 240.103, found [M+H] 241.1.

8F. 5-Chloro-2-ethyl-4-(4-(4-iodophenoxy)piperidin-1-yl)pyridine

To a solution of 8E (180 mg, 0.75 mmol) and 4-iodophenol (330 mg, 1.5mmol) in toluene (12 mL) was added Bu₃P (0.30 mL, 1.2 mmol) followed byADDP (300 mg, 1.2 mmol). The reaction mixture was stirred at 50° C. for3 h and then at rt overnight. The reaction mixture was treated with 2:1toluene/hexanes (10 mL), filtered, and the solid was washed with 2:1toluene/hexanes. The filtrate was concentrated. Purification of thecrude product via silica chromatography yielded 8F (186 mg, 0.420 mmol,56% yield). LC-MS Anal. Calc'd for C₁₈H₂₀ClIN₂O: 442.031, found [M+H]443.0. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.58-7.55 (m, 2H),6.74-6.70 (m, 3H), 4.51-4.48 (m, 1H), 3.42-3.37 (m, 2H), 3.16-3.10 (m,2H), 2.76-2.71 (m, 2H), 2.14-2.09 (m, 4H), 1.28 (t, J=7.7, 7.7 Hz, 3H).

8G.((2R,3S,4R)-1-(4-((1-(5-Chloro-2-ethylpyridin-4-yl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol

To a solution of 8F (180 mg, 0.41 mmol) and 1H (70 mg, 0.34 mmol) inn-BuOH (1.7 mL) was added NaOH (48 mg, 1.2 mmol) and CuI (6.6 mg, 0.034mmol). The reaction mixture was purged with argon and the reaction vialwas sealed and stirred at 90° C. for 17 h. The mixture was poured intosat. aq. NH₄Cl, and extracted with CH₂Cl₂. The combined extracts werewashed with brine, dried (MgSO₄), and concentrated. Purification viasilica chromatography yielded 8G (140 mg, 0.270 mmol, 78% yield). LC-MSAnal. Calc'd for C₂₈H₄₀ClN₃O₄: 517.271, found [M+H] 518.3.

8H.((2R,3S,4R)-1-(4-((1-(5-Chloro-2-ethylpyridin-4-yl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methylmethanesulfonate

To a solution of 8G (160 mg, 0.31 mmol) in CH₂Cl₂ (3.1 mL) at 0° C.,NEt₃ (0.11 mL, 0.77 mmol) was added followed by MsCl (0.040 mL, 0.53mmol). The reaction mixture was stirred at 0° C. for 0.5 h. The reactionmixture was diluted with CH₂Cl₂. The organic layer was washed with waterand brine, dried over MgSO₄, filtered, and concentrated to give themesylate, which was used in the next step without purification. To asolution of the crude material in DMSO (1.5 mL), NaCN (45 mg, 0.93 mmol)was added. The reaction mixture was stirred at 50° C. for 3 h. Thereaction mixture was diluted with EtOAc, washed with aq. NaHCO₃, water,and brine, dried (MgSO₄), and concentrated. Purification via silicachromatography yielded 8H (131 mg, 0.249 mmol, 81% yield). LC-MS Anal.Calc'd for C₂₉H₃₉ClN₄O₃: 526.271, found [M+H]527.3. ¹H NMR (400 MHz,CDCl₃) δ 8.31 (s, 1H), 6.92-6.89 (m, 2H) 6.72 (s, 1H), 6.51-6.49 (m,2H), 4.35 (br. s, 1H), 3.76-3.42 (m, 10H), 3.33 (s, 3H), 3.11-2.71 (m,6H), 2.09-1.82 (m, 6H), 1.30-1.27 (m, 4H), 1.06 (d, J=7.4 Hz, 3H).

8I. Methyl2-((2S,3S,4R)-1-(4-((1-(5-chloro-2-ethylpyridin-4-yl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetate

A 3 M HCl/MeOH/CH₂Cl₂/MeOAc solution [25.2 mL, prepared by addition ofAcCl (5.2 mL) to a 3/2 CH₂Cl₂/MeOH solution (20 mL) at 0° C. and thenstirring at rt for 20 min] was added to 8H (130 mg, 0.25 mmol). Thereaction mixture was allowed to stand for 16 h at rt. The reactionmixture was concentrated and rotovapped down with MeOH (2×). Then a 3 MHCl/MeOH solution [25.2 mL, prepared by addition of AcCl (5.2 mL) to a3/2 CHCl₂/MeOH solution (20 mL) at 0° C. and then stirring at rt for 20min] was added to the mixture, which was heated to 40° C. for 24 hwithout stirring. The reaction mixture was concentrated and diluted withEtOAc. The organic layer was washed with aq. NaHCO₃, water, and brine,dried (MgSO₄), and concentrated. Purification via silica chromatographyyielded 81 (118 mg, 0.211 mmol, 85% yield). LC-MS Anal. Calc'd forC₃₀H₄₂ClN₃O₅: 559.28, found [M+H] 560.4. ¹H NMR (400 MHz, CDCl₃) δ 8.30(s, 1H), 6.91-6.88 (m, 2H) 6.72 (s, 1H), 6.53-6.51 (m, 2H), 4.32 (br. s,1H), 3.72-3.42 (m, 13H), 3.33 (s, 3H), 3.10-2.70 (m, 6H), 2.08-1.81 (m,7H), 1.30-1.26 (t, J=7.6, 7.6 Hz, 3H), 1.02-1.00 (m, 3H).

Example 8

To a solution of 81 (70 mg, 0.13 mmol) in THF (3.5 mL), 1 N aq. LiOH(0.75 mL, 0.75 mmol) was added. The reaction mixture was stirred at rtfor 24 h. The mixture was cooled to 0° C., neutralized to pH<7 with 1 Naq. HCl, and extracted with CH₂Cl₂. The combined organic layers weredried (MgSO₄), filtered, and concentrated. The residue was purified viaRP-Prep. HPLC. The product was treated with CH₃CN (5 mL) and 1 N aq. HCl(0.3 mL) and concentrated. The procedure was repeated (2×) to yieldExample 8 (0.011 g, 0.018 mmol, 14% yield) as an off-white solid. LC-MSAnal. Calc'd for C₂₉H₄₀ClN₃O₅: 545.266, found [M+H] 546.3. ¹H NMR (400MHz, D₂O) δ 8.20 (s, 1H), 7.47-7.45 (d, J=8.3 Hz, 2H) 7.15-7.14 (d,J=9.1 Hz, 2H), 7.04 (s, 1H), 4.79 (br. s, 1H), 4.09 (br. s, 1H),3.95-3.80 (m, 5H), 3.60-3.51 (m, 6H), 3.33 (s, 3H), 2.79-2.69 (m, 4H),2.31 (m, 1H), 2.17-2.13 (m, 2H), 1.93-1.82 (m, 4H), 1.25-1.22 (m, 6H).Analytical HPLC: RT=5.8 min, HI: 97.0%. hGPR40 EC₅₀=1100 nM.

Example 92-((2S,3S,4R)-1-(6-(((3,4-trans)-1-(5-Ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid, HCl

9A. 5-Ethoxy-2-fluoroaniline

To a solution of (5-ethoxy-2-fluorophenyl) boronic acid (10.1 g, 55.0mmol) in MeOH (220 mL) was added 14.8 M aq. NH₄OH (18.6 mL, 275 mmol)and then cuprous oxide (1.57 g, 11.0 mmol). The reaction mixture wasstirred under air for 7 h. The reaction mixture was concentrated. Thecrude product was dissolved in EtOAc/hexanes (2:1). The material wasfiltered through CELITE® and concentrated. The crude material waspurified by silica chromatography to provide 9A (4.10 g, 26.4 mmol, 48%yield) as a brown oil. LC-MS Anal. Calc'd for C₈H₁₀FNO: 155.17, found[M+H] 156.1. ¹H NMR (400 MHz, CDCl₃) δ 6.86 (dd, J=10.9, 8.8 Hz, 1H),6.32 (dd, J=7.5, 2.9 Hz, 1H), 6.20 (dt, J=8.8, 3.3 Hz, 1H), 3.94 (q,J=6.9 Hz, 2H), 3.68 (br. s, 2H), 1.37 (t, J=6.9 Hz, 3H).

9B. 1-Benzyl-1,3-dimethyl-4-oxopiperidin-1-ium, iodide salt

To a solution of 1-benzyl-3-methylpiperidin-4-one (14.0 g, 68.9 mmol) inacetone (68.9 mL) at rt was added MeI (8.61 mL, 138 mmol) dropwise. Thereaction mixture was stirred at rt overnight and then concentrated toobtain 9B (24.0 g, 69.5 mmol, 101% yield) as a light yellow foam. LC-MSAnal. Calc'd for C₁₄H₂₀NO: 218.15, found [M+H] 219.2.

9C. 1-(5-Ethoxy-2-fluorophenyl)-3-methylpiperidin-4-one

To a solution of 9A (7.87 g, 50.7 mmol) in EtOH (103 mL) was added K₂CO₃(1.05 g, 7.61 mmol), 9B (26.3 g, 76.0 mmol), and water (46.6 mL). Thereaction mixture was heated to 95° C. overnight. The reaction mixturewas cooled to rt and diluted with EtOAc/water. The layers were separatedand the aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried (MgSO₄), and concentrated.The crude product was purified by silica chromatography to provide 9C(10.1 g, 40.3 mmol, 79% yield) as a colorless oil, which solidifiedovernight. LC-MS Anal. Calc'd for C₁₄H₁₈FNO₂: 251.13, found [M+H] 252.2.¹H NMR (400 MHz, CDCl₃) δ 6.95 (dd, J=12.1, 8.8 Hz, 1H), 6.52 (dd,J=7.5, 2.9 Hz, 1H), 6.44 (dt, J=8.8, 3.2 Hz, 1H), 3.98 (q, J=7.3 Hz,2H), 3.75-3.64 (m, 2H), 3.12 (td, J=11.7, 3.5 Hz, 1H), 2.85-2.69 (m,3H), 2.49 (dt, J=14.1, 3.3 Hz, 1H), 1.40 (t, J=6.9 Hz, 3H), 1.09 (d,J=6.1 Hz, 3H).

9D. (3,4-cis)-1-(5-Ethoxy-2-fluorophenyl)-3-ethylpiperidin-4-ol

To a solution of 9C (4.920 g, 19.58 mmol) in THF (98 mL) at −78° C. wasadded a 1 M solution of L-Selectride (23.5 mL, 23.5 mmol) in THF. After1 h, the reaction mixture was quenched with 1 M aq. NaOH (23.5 mL, 23.5mmol) and warmed to 0° C. 30% aq. H₂O₂(7.4 mL, 72 mmol) was addeddropwise and the reaction mixture was warmed to rt and stirred for 1 h.The reaction mixture was diluted with EtOAc/water and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×). The combinedorganic layers were washed with brine, dried (MgSO₄), and concentrated.The crude product was purified by silica chromatography to provide 9D(4.453 g, 17.58 mmol, 90% yield) as a colorless oil. LC-MS Anal. Calc'dfor C₁₄H₂₀FNO₂: 253.31, found [M+H] 254.0. ¹H NMR (500 MHz, CDCl₃) δ6.89 (dd, J=12.1, 8.8 Hz, 1H), 6.52 (dd, J=7.3, 2.9 Hz, 1H), 6.37 (dt,J=8.8, 3.2 Hz, 1H), 3.97 (q, J=7.1 Hz, 2H), 3.90 (br. s, 1H), 3.13-3.02(m, 2H), 3.02-2.95 (m, 1H), 2.84 (dd, J=11.4, 9.8 Hz, 1H), 2.05 (dqt,J=10.1, 6.7, 3.6 Hz, 1H), 2.00-1.91 (m, 1H), 1.91-1.83 (m, 1H), 1.50(br. s, 1H), 1.38 (t, J=6.9 Hz, 3H), 1.03 (d, J=6.9 Hz, 3H).

9E. (3,4-cis)-1-(5-Ethoxy-2-fluorophenyl)-3-methylpiperidin-4-ol, Isomer2

9D (29.2 g, 115 mmol) was purified by chiral SFC to give 9E as singleisomers. 9E, Isomer 2 (13.5 g, 53.5 mmol, 47% yield) was obtained as acolorless oil after concentration. LC-MS Anal. Calc'd for C₁₄H₁₈FNO₂:251.13, found [M+H] 252.2. ¹H NMR (400 MHz, CDCl₃) δ 6.95 (dd, J=12.1,8.8 Hz, 1H), 6.52 (dd, J=7.5, 2.9 Hz, 1H), 6.44 (dt, J=8.8, 3.2 Hz, 1H),3.98 (q, J=7.3 Hz, 2H), 3.75-3.64 (m, 2H), 3.12 (td, J=11.7, 3.5 Hz,1H), 2.85-2.69 (m, 3H), 2.49 (dt, J=14.1, 3.3 Hz, 1H), 1.40 (t, J=6.9Hz, 3H), 1.09 (d, J=6.1 Hz, 3H).

Example 9 (yellow solid, 29.3 mg) was prepared as a single isomer from9E and 5-iodopyridin-2-ol following the procedure of Example 2. LC-MSAnal. Calc'd for C₃₀H₄₂FN₃O₆: 559.67, found [M+H] 560.2. ¹H NMR (500MHz, CD₃CN) δ 8.01 (br. s, 1H), 7.77 (d, J=6.4 Hz, 1H), 7.53 (br. s,1H), 7.38 (d, J=7.0 Hz, 1H), 7.28 (dd, J=11.6, 9.4 Hz, 1H), 7.03 (d,J=8.6 Hz, 1H), 5.01-4.83 (m, 1H), 4.05 (q, J=6.8 Hz, 2H), 4.00-3.89 (m,1H), 3.88-3.78 (m, 3H), 3.72 (d, J=9.7 Hz, 1H), 3.64-3.45 (m, 5H), 3.40(t, J=6.3 Hz, 2H), 3.25 (s, 3H), 3.09-2.93 (m, 1H), 2.74 (d, J=6.2 Hz,2H), 2.70-2.58 (m, 1H), 2.58-2.47 (m, 1H), 2.46-2.37 (m, 1H), 1.76(quin, J=6.2 Hz, 2H), 1.37 (t, J=6.7 Hz, 3H), 1.14 (d, J=5.7 Hz, 3H),0.98 (d, J=7.3 Hz, 3H). Analytical HPLC: RT=9.1 min, HI: 95.5%. hGPR40EC₅₀=170 nM. hGPR40 IP1 EC₅₀=35 nM.

Example 102-((2R,4R)-1-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropyl)pyrrolidin-2-yl)aceticacid, TFA

10A. (R)-1-Benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate

To a solution of (2R,4R)-1-Benzyl 2-methyl4-hydroxypyrrolidine-1,2-dicarboxylate (16.7 g, 59.7 mmol) in CH₂Cl₂(149 mL) was added TCCA (13.9 g, 59.7 mmol) followed by the addition ofTEMPO (0.093 g, 0.60 mmol). The reaction mixture was warmed to rt andstirred for 15 min. The reaction mixture was filtered and washed withsat. Na₂CO₃, 0.1 M aq. HCl, and brine. The organic layer was dried(MgSO₄) and concentrated. The material was filtered through a plug ofsilica gel to obtain 10A (12.6 g, 45.3 mmol, 76% yield) as a colorlessoil, which solidified upon standing to a pale yellow solid. LC-MS Anal.Calc'd for C₁₄H₁₅NO₅: 277.27, found [M+H] 278.0. ¹H NMR (500 MHz, CDCl₃)δ 7.43-7.28 (m, 5H), 5.27-5.20 (m, 1H), 5.19-5.08 (m, 1H), 4.92-4.78 (m,1H), 4.07-3.88 (m, 2H), 3.81-3.56 (m, 3H), 3.03-2.87 (m, 1H), 2.61 (dd,J=18.8, 2.6 Hz, 1H).

10B. (R)-7-Benzyl 8-methyl1,4-dioxa-7-azaspiro[4.4]nonane-7,8-dicarboxylate

10A (12.6 g, 45.3 mmol) and ethane-1,2-diol (2.5 mL, 45 mmol) weredissolved in toluene (450 mL). TsOH (1.01 g, 5.89 mmol) was added. Theresulting mixture was heated to reflux for 18 h. The reaction mixturewas cooled to rt, poured into ice water, extracted with EtOAc (3×),washed with brine, dried (MgSO₄), and concentrated. The crude productwas purified by silica chromatography to provide 10B (8.58 g, 26.7 mmol,59% yield) as a pale yellow oil, which solidified upon standing. LC-MSAnal. Calc'd for C₁₆H₁₉NO₆: 321.33, found [M+H] 322.0. ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.27 (m, 5H), 5.25-4.99 (m, 2H), 4.60-4.42 (m, 1H),4.02-3.87 (m, 4H), 3.82-3.53 (m, 5H), 2.48-2.34 (m, 1H), 2.29-2.17 (m,1H).

10C.(S)-2-(7-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)acetonitrile

10C was prepared from 10B and 3C following the procedure of Example 1.LC-MS Anal. Calc'd for C₂₇H₃₂FN₃O₄: 481.56, found [M+H] 482.2. ¹H NMR(500 MHz, CDCl₃) δ 6.95-6.87 (m, 3H), 6.53 (dd, J=7.4, 3.0 Hz, 1H),6.51-6.45 (m, 2H), 6.40 (dt, J=8.8, 3.2 Hz, 1H), 4.29 (tt, J=7.4, 3.6Hz, 1H), 4.23-4.16 (m, 1H), 4.10-4.05 (m, 1H), 4.05-4.01 (m, 1H),4.01-3.95 (m, 4H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 3.37-3.30 (m,2H), 2.94 (ddd, J=11.8, 8.3, 3.3 Hz, 2H), 2.80-2.75 (m, 1H), 2.75-2.68(m, 1H), 2.46 (dd, J=13.3, 8.1 Hz, 1H), 2.22 (dd, J=13.2, 1.4 Hz, 1H),2.12-2.05 (m, 2H), 1.99-1.90 (m, 2H), 1.39 (t, J=7.0 Hz, 3H).

10D.(S)-2-(1-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-oxopyrrolidin-2-yl)acetonitrile

To a solution of 10C (1.36 g, 2.82 mmol) in acetone (39 mL) and water(17 mL) (purged with argon for 10 min) was added TsOH (2.14 g, 11.3mmol). The reaction mixture was heated to 56° C. for 30 h. The reactionmixture was cooled to rt and diluted with EtOAc/water. 1.5 M aq. K₂HPO₄was added to basify the reaction mixture and the layers were separated.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with brine, dried (MgSO₄), and concentrated. 10D(1.16 g, 2.66 mmol, 94% yield) was isolated as a light brown solid andwas used without further purification. LC-MS Anal. Calc'd forC₂₅H₂₈FN₃O₃: 437.51, found [M+H] 438.1. ¹H NMR (400 MHz, CDCl₃) δ7.00-6.95 (m, 2H), 6.91 (dd, J=12.1, 8.8 Hz, 1H), 6.67-6.61 (m, 2H),6.54 (dd, J=7.4, 3.0 Hz, 1H), 6.40 (dt, J=8.8, 3.1 Hz, 1H), 4.58 (tt,J=8.0, 2.9 Hz, 1H), 4.34 (tt, J=7.4, 3.7 Hz, 1H), 3.98 (q, J=6.9 Hz,2H), 3.86-3.71 (m, 2H), 3.39-3.28 (m, 2H), 3.05 (dd, J=18.6, 8.5 Hz,1H), 2.96 (ddd, J=11.9, 8.1, 3.3 Hz, 2H), 2.72 (ddd, J=17.6, 12.3, 2.5Hz, 2H), 2.57 (dd, J=16.8, 7.6 Hz, 1H), 2.16-2.06 (m, 2H), 2.02-1.89 (m,2H), 1.40 (t, J=6.9 Hz, 3H).

10E.(S)-5-(Cyanomethyl)-1-(4-((1-(5-ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yltrifluoromethanesulfonate

To a 1 M solution of NaHMDS (0.75 mL, 0.75 mmol) in THF (3.4 mL) at −78°C. was added a solution of 10D (0.300 g, 0.686 mmol) in THF (3.4 mL)dropwise. The reaction mixture was stirred for 30 min and then asolution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonylmethanesulfonamide (0.294 g, 0.823 mmol) in THF (3.4 mL) was addeddropwise. The reaction mixture was stirred for 2 h at −78° C. Thereaction mixture was quenched with 1.5 M aq. K₂HPO₄ and extracted withEtOAc (2×). The combined organic layers were washed with brine, dried(MgSO₄), and concentrated. The crude product was purified by silicachromatography to provide 10E (0.309 g, 0.543 mmol, 79% yield) as acolorless oil. LC-MS Anal. Calc'd for C₂₆H₂₇F₄N₃O₅S: 569.57, found [M+H]570.0. ¹H NMR (400 MHz, CDCl₃) δ 6.98-6.86 (m, 3H), 6.58-6.49 (m, 3H),6.40 (dt, J=8.8, 3.2 Hz, 1H), 5.93 (q, J=1.8 Hz, 1H), 4.93-4.83 (m, 1H),4.53 (ddd, J=13.3, 6.7, 1.9 Hz, 1H), 4.36-4.27 (m, 1H), 4.22-4.15 (m,1H), 3.98 (q, J=7.0 Hz, 2H), 3.39-3.28 (m, 2H), 2.95 (ddd, J=11.8, 8.2,3.3 Hz, 2H), 2.82-2.78 (m, 2H), 2.15-2.05 (m, 2H), 2.01-1.88 (m, 2H),1.40 (t, J=6.9 Hz, 3H).

10F.(S,E)-2-(1-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxyprop-1-en-1-yl)-2,5-dihydro-1H-pyrrol-2-yl)acetonitrile

To a solution of 10E (0.035 g, 0.062 mmol), and(E)-2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.013 mL, 0.062 mmol) in dioxane (0.63 mL) was added a solution ofNa₂CO₃ (0.016 g, 0.16 mmol) in water (0.063 mL). The reaction mixturewas purged with argon for 10 min and then Pd(Ph₃P)₄ (1.4 mg, 1.2 μmol)was added. The reaction mixture was microwaved at 150° C. for 3 min. Thereaction mixture was diluted with EtOAc/water and the layers wereseparated. The organic layer was washed with brine, dried (MgSO₄), andconcentrated. The crude product was purified by silica chromatography toprovide 10F (0.011 g, 0.023 mmol, 37% yield). LC-MS Anal. Calc'd forC₂₉H₃₄FN₃O₃: 491.60, found [M+H] 492.2. ¹H NMR (500 MHz, CDCl₃) δ6.96-6.87 (m, 3H), 6.57-6.52 (m, 3H), 6.48 (d, J=16.0 Hz, 1H), 6.40 (dt,J=8.8, 3.2 Hz, 1H), 5.90 (s, 1H), 5.80 (dt, J=16.0, 5.6 Hz, 1H),4.84-4.78 (m, 1H), 4.49 (ddd, J=12.9, 5.6, 1.4 Hz, 1H), 4.29 (tt, J=7.4,3.7 Hz, 1H), 4.14 (d, J=12.9 Hz, 1H), 4.04 (d, J=5.8 Hz, 2H), 3.98 (q,J=7.1 Hz, 2H), 3.38 (s, 3H), 3.37-3.31 (m, 2H), 2.95 (ddd, J=11.8, 8.2,3.2 Hz, 2H), 2.81 (dd, J=16.6, 3.2 Hz, 1H), 2.64 (dd, J=16.6, 7.0 Hz,1H), 2.10 (tdd, J=7.5, 3.6, 1.8 Hz, 2H), 2.00-1.92 (m, 2H), 1.40 (t,J=7.0 Hz, 3H).

Example 10

To a solution of 10E (0.011 g, 0.023 mmol) in MeOH (2 mL) and EtOAc (2mL) was added 10% Pd/C (2.4 mg, 2.3 μmol). The reaction mixture waspurged with argon (3×) and then H₂ (3×) and stirred under H₂ (1 atm) atrt overnight. The reaction mixture was filtered and concentrated toprovide 9G (0.0100 g, 0.020 mmol, 89% yield) as a pale yellow oil. Thecrude material was dissolved in EtOH (0.28 mL) and a 6 M aq. solution ofKOH (0.092 mL, 0.55 mmol) was added. The reaction was sealed and heatedat 120° C. for 2 h. The reaction mixture was concentrated andredissolved in EtOAc. The solution was acidified to pH 2 with 1 N aq.HCl and the product was extracted with EtOAc (3×). The combined organiclayers were dried (MgSO₄) and concentrated. The crude product waspurified by RP-Prep. HPLC. The HPLC fractions were rotovapped to removethe CH₃CN and then the aqueous layer was extracted with CH₂Cl₂ (3×). Thecombined organic layers were dried (MgSO₄) and concentrated. The residuewas dissolved in CH₃CN and 0.5 mL of 3 N aq. HCl was added. The reactionmixture was concentrated and the procedure was repeated (2×). Theaqueous layer was lyophilized overnight to give Example 10 (0.0044 g,6.7 μmol, 24% yield) as a colorless oil. LC-MS Anal. Calc'd forC₂₉H₃₉FN₂O₅: 514.63, found [M+H]515.3. ¹H NMR (500 MHz, CD₃CN) δ 7.41(d, J=8.0 Hz, 2H), 7.10 (d, J=9.1 Hz, 2H), 7.00 (dd, J=12.4, 8.8 Hz,1H), 6.64 (dd, J=7.2, 3.0 Hz, 1H), 6.52 (dt, J=8.9, 3.3 Hz, 1H), 4.58(br. s, 1H), 4.18-4.08 (m, 1H), 4.02 (q, J=6.9 Hz, 2H), 3.67 (d, J=6.9Hz, 2H), 3.43-3.33 (m, 4H), 3.30 (s, 3H), 3.05 (ddd, J=12.0, 8.5, 3.2Hz, 2H), 2.81-2.72 (m, 1H), 2.72-2.57 (m, 3H), 2.21-2.11 (m, 2H),1.94-1.86 (m, 2H), 1.74-1.65 (m, 1H), 1.65-1.53 (m, 4H), 1.36 (t, J=7.0Hz, 3H). Analytical HPLC: RT=7.1 min, HI: 95.1%. hGPR40 EC₅₀=380 nM.hGPR40 IP1 EC₅₀=47 nM.

Example 112-((2R,4R)-1-(4-(((3,4-trans)-1-(5-Ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)pyrrolidin-2-yl)aceticacid, HCl

11A. (2R,4R)-tert-Butyl4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate

(2R,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(6.98 g, 30.2 mmol) was dissolved in anhydrous THE (123 mL) and cooledto −10° C. 4-Methylmorpholine (3.5 mL, 32 mmol) and isobutylchloroformate (4.2 mL, 32 mmol) were then added and the reaction mixturewas stirred at −10° C. for 45 min. The reaction mixture was filtered andadded dropwise to a solution of NaBH₄ (2.28 g, 60.4 mmol) in water (16mL) cooled to 0° C. The reaction mixture was stirred for 2 h and slowlywarmed to rt. The reaction mixture was quenched with sat. aq. NH₄Cl andthe product was extracted with EtOAc (3×). The combined organic layerswere washed with brine, dried (MgSO₄), and concentrated. The crudeproduct was purified by silica chromatography to provide 11A (5.98 g,27.5 mmol, 91% yield) as a colorless oil, which solidified to a whitesolid upon standing. LC-MS Anal. Calc'd for C₁₀H₁₉NO₄: 217.26, found[M+H] 218.0. ¹H NMR (500 MHz, CDCl₃) δ 4.35-4.09 (m, 2H), 4.09-3.88 (m,2H), 3.67-3.33 (m, 3H), 2.44-2.24 (m, 1H), 2.07-1.71 (m, 2H), 1.53-1.40(m, 9H).

11B. (2R,4R)-tert-Butyl2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylate

To a solution of 11A (3.00 g, 13.8 mmol) in DMF (69 mL) was addedTBDPS-Cl (3.9 mL, 15 mmol) and imidazole (1.41 g, 20.7 mmol). Thereaction mixture was stirred at rt for 2 h. The reaction mixture wasdiluted with EtOAc and washed with water (5×). The organic layer waswashed with brine, dried (MgSO₄), and concentrated. The crude productwas purified by silica chromatography to give 11B (2.58 g, 5.66 mmol,41% yield) as a colorless oil. LC-MS Anal. Calc'd for C₂₆H₃₇NO₄Si:455.66, found [M+H] 456.1. ¹H NMR (500 MHz, CDCl₃) δ 7.72-7.60 (m, 4H),7.48-7.34 (m, 6H), 4.78 (d, J=11.0 Hz, 0.5H), 4.50 (d, J=10.2 Hz, 0.5H),4.37-4.20 (m, 1.5H), 4.01 (br. s, 1H), 3.89 (d, J=9.4 Hz, 0.5H),3.62-3.42 (m, 3H), 2.45-2.29 (m, 1H), 2.12-1.96 (m, 1H), 1.54-1.43 (s,4.5H), 1.29 (s, 4.5H), 1.08 (s, 9H).

11C. (2R,4R)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(3-methoxypropoxy)pyrrolidine-1-carboxylate

To a solution of 11B (0.098 g, 0.22 mmol) in THF (2.2 mL) at 0° C. wasadded 60% NaH (0.060 g, 1.5 mmol). The reaction mixture was stirred for30 min and then 1-bromo-3-methoxypropane (0.17 mL, 1.5 mmol) was added.The reaction mixture was warmed to rt and refluxed overnight. Thereaction mixture was quenched with water and diluted with EtOAc. Thelayers were separated and the aqueous layer was extracted with EtOAc.The combined organic layers were washed with brine, dried (MgSO₄), andconcentrated. The crude product was purified by silica chromatography toprovide 11C (0.028 g, 0.053 mmol, 25% yield) as a colorless oil. LC-MSAnal. Calc'd for C₃₀H₄₅NO₅Si: 527.77, found [M+H] 528.3. ¹H NMR (400MHz, CDCl₃) δ 7.73-7.60 (m, 4H), 7.46-7.30 (m, 6H), 3.99 (br. s, 1H),3.94-3.74 (m, 2H), 3.71-3.59 (m, 2H), 3.52-3.36 (m, 4H), 3.36-3.31 (m,1H), 3.30 (s, 3H), 2.49-2.22 (m, 1H), 2.15-2.02 (m, 1H), 1.83-1.70 (m,2H), 1.49-1.25 (m, 9H), 1.06 (s, 9H).

11D. (2R,4R)-tert-Butyl 2-(hydroxymethyl)-4-(3-methoxypropoxy)pyrrolidine-1-carboxylate

To a solution of 11C (0.367 g, 0.696 mmol) in THF (3.5 mL) at rt wasadded a 1 M solution of TBAF (1.0 mL, 1.0 mmol) in THF. The reactionmixture was stirred at rt overnight. The reaction mixture was dilutedwith EtOAc/water and the layers were separated. The aqueous layer wasextracted with EtOAc and the combined organic layers were washed withbrine, dried (MgSO₄), and concentrated. The crude product was purifiedby silica chromatography to provide 11D (0.187 g, 0.647 mmol, 93% yield)as a colorless oil. LC-MS Anal. Calc'd for C₁₄H₂₇NO₅: 289.37, found[M+H] 290.1. ¹H NMR (500 MHz, CDCl₃) δ 4.43 (d, J=6.9 Hz, 1H), 4.11-4.02(m, 1H), 4.02-3.90 (m, 1H), 3.87-3.58 (m, 2H), 3.57-3.47 (m, 3H),3.47-3.37 (m, 3H), 3.33 (s, 3H), 2.18 (m, 1H), 1.82 (quin, J=6.3 Hz,2H), 1.46 (s, 9H).

11E. ((2R,4R)-4-(3-Methoxypropoxy)pyrrolidin-2-yl)methanol, HCl

A 4 N solution of HCl (1.00 mL, 4.00 mmol) in dioxane was added to 11D(0.079 g, 0.27 mmol). The reaction mixture was stirred at rt for 1 h.The reaction mixture was concentrated and rotovapped with MeOH (2×) toprovide 11E (0.062 g, 0.27 mmol, 100% yield) as a colorless oil. LC-MSAnal. Calc'd for C₉H₁₉NO₃: 189.25, found [M+H] 190.0.

11F.(3,4-trans)-1-(5-Ethoxy-2-fluorophenyl)-4-(4-iodophenoxy)-3-methylpiperidine

To a solution of 9E (0.511 g, 2.02 mmol), 4-iodophenol (0.577 g, 2.62mmol), and Bu₃P (0.80 mL, 3.2 mmol) in toluene (25 mL) was added ADDP(0.815 g, 3.23 mmol). The reaction mixture was sonicated for 99 min. Thereaction mixture was poured into hexanes, filtered, and concentrated.The crude product was purified by silica chromatography to provide 11F(0.643 g, 1.41 mmol, 70% yield) as a colorless oil. LC-MS Anal. Calc'dfor C₂₀H₂₃FINO₂: 455.31, found [M+H] 456.2. ¹H NMR (400 MHz, CDCl₃) δ7.62-7.49 (m, 2H), 6.91 (dd, J=12.1, 8.8 Hz, 1H), 6.76-6.67 (m, 2H),6.50 (dd, J=7.5, 2.9 Hz, 1H), 6.40 (dt, J=8.8, 3.2 Hz, 1H), 3.98 (q,J=6.9 Hz, 2H), 3.89 (td, J=9.0, 4.0 Hz, 1H), 3.51-3.36 (m, 2H), 2.81(td, J=11.5, 2.8 Hz, 1H), 2.57 (dd, J=12.1, 9.6 Hz, 1H), 2.22-2.08 (m,2H), 1.90-1.75 (m, 1H), 1.40 (t, J=6.9 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H).

Example 11 (beige solid, 25 mg) was prepared as a single isomer from 11Eand 11F following the procedure of Example 1. LC-MS Anal. Calc'd forC₃₀H₄₁FN₂O₆: 544.66, found [M+H] 545.3. ¹H NMR (500 MHz, CD₃CN) δ 7.80(br. s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.21 (dd, J=12.1, 9.1 Hz, 1H), 7.11(d, J=9.1 Hz, 2H), 6.92 (dt, J=9.0, 3.1 Hz, 1H), 4.50-4.43 (m, 1H), 4.33(td, J=9.8, 4.7 Hz, 1H), 4.21-4.12 (m, 1H), 4.03 (q, J=6.9 Hz, 2H), 3.83(dd, J=12.4, 3.3 Hz, 1H), 3.74-3.63 (m, 3H), 3.62-3.56 (m, 1H), 3.51(tq, J=6.3, 3.0 Hz, 2H), 3.46-3.41 (m, 2H), 3.37 (t, J=12.1 Hz, 1H),3.27 (s, 3H), 3.01-2.92 (m, 1H), 2.92-2.84 (m, 1H), 2.78 (dt, J=13.4,6.6 Hz, 2H), 2.46-2.28 (m, 2H), 2.15-2.05 (m, 1H), 1.77 (quin, J=6.3 Hz,2H), 1.36 (t, J=6.9 Hz, 3H), 1.08 (d, J=6.6 Hz, 3H). Analytical HPLC:RT=10.5 min, HI: 97.3%. hGPR40 EC₅₀=100 nM. hGPR40 IP1 EC₅₀=16 nM.

Example 122-((2R,4R)-1-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)pyrrolidin-2-yl)aceticacid, HCO₂H

Example 12 (9.5 mg) was prepared from 11E and 3C following the procedureof Example 1. LC-MS Anal. Calc'd for C₂₉H₃₉FN₂O₆: 530.63, found [M+H]531.2. ¹H NMR (500 MHz, DMSO-d₆) δ 7.00 (dd, J=12.0, 9.2 Hz, 1H), 6.88(d, J=8.0 Hz, 2H), 6.52 (d, J=7.7 Hz, 1H), 6.50 (d, J=8.3 Hz, 2H),6.47-6.43 (m, 1H), 4.31-4.24 (m, 1H), 4.16-4.11 (m, 1H), 4.01-3.93 (m,3H), 3.52-3.42 (m, 2H), 3.41-3.22 (m, 6H), 3.21 (s, 3H), 2.91-2.83 (m,2H), 2.62 (d, J=15.1 Hz, 1H), 2.43 (dd, J=15.0, 10.6 Hz, 1H), 2.14 (dt,J=13.4, 6.6 Hz, 1H), 2.04-1.95 (m, J=13.2 Hz, 3H), 1.78-1.67 (m, 4H),1.29 (t, J=6.9 Hz, 3H). Analytical HPLC (Acquity method): RT=1.8 min,HI: 98.3%. hGPR40 EC₅₀=160 nM. hGPR40 IP1 EC₅₀=39 nM.

Example 132-((2R,4R)-1-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-4-(2-methoxyethoxy)pyrrolidin-2-yl)aceticacid, TFA

Example 13 (yellow oil, 13.6 mg) was prepared from1-bromo-2-methoxyethane and 3C following the procedure of Example 11.LC-MS Anal. Calc'd for C₂₈H₃₇FN₂O₆: 516.26, found [M+H] 517.1. ¹H NMR(400 MHz, DMSO-d₆) δ 7.01 (dd, J=8.8, 12.5 Hz, 1H), 6.89 (d, J=9.0 Hz,2H), 6.56-6.44 (m, 4H), 4.32-4.24 (m, 1H), 4.19 (t, J=4.9 Hz, 1H),4.03-3.95 (m, 1H), 3.97 (q, J=7.0 Hz, 2H), 3.63-3.50 (m, 2H), 3.49-3.44(m, 2H), 3.30-3.23 (m, 3H), 3.28 (s, 3H), 2.92-2.84 (m, 2H), 2.69-2.58(m, 1H), 2.48-2.43 (m, 2H), 2.19-2.10 (m, 1H), 2.06-1.95 (m, 3H),1.77-1.67 (m, 2H), 1.30 (t, J=7.0 Hz, 3H). Analytical HPLC (12 mingradient, 15 min stop): RT=10.1 min, HI: 98.0%. hGPR40 EC₅₀=1000 nM.

Example 142-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid, HCl

Example 14 (tan solid, 38.0 mg) was prepared as a single isomer from 11Ffollowing the procedure of Example 1. LC-MS Anal. Calc'd forC₃₁H₄₃FN₂O₆: 558.68, found [M+H] 559.2. ¹H NMR (500 MHz, CD₃CN) δ 8.04(dd, J=6.1, 3.0 Hz, 1H), 7.83 (d, J=9.1 Hz, 2H), 7.27 (dd, J=12.1, 9.1Hz, 1H), 7.13 (d, J=9.1 Hz, 2H), 7.02 (dt, J=9.2, 3.4 Hz, 1H), 4.41 (td,J=10.2, 4.1 Hz, 1H), 4.11-4.01 (m, 3H), 3.93 (dt, J=11.3, 5.6 Hz, 1H),3.87 (td, J=12.4, 2.6 Hz, 1H), 3.83-3.75 (m, 2H), 3.72 (d, J=12.1 Hz,1H), 3.68-3.61 (m, 1H), 3.58-3.49 (m, 3H), 3.43 (td, J=6.3, 1.1 Hz, 2H),3.26 (s, 3H), 3.05-2.97 (m, 1H), 2.97-2.88 (m, 1H), 2.81 (dd, J=17.3,5.5 Hz, 1H), 2.58-2.46 (m, 1H), 2.45-2.33 (m, 2H), 1.77 (quin, J=6.3 Hz,2H), 1.37 (t, J=7.0 Hz, 3H), 1.20 (d, J=6.9 Hz, 3H), 1.09 (d, J=6.6 Hz,3H). Analytical HPLC: RT=11.2 min, HI: 95.8%. hGPR40 EC₅₀=51 nM. hGPR40IP1 EC₅₀=7 nM.

Example 16 2-((2S,3S,4R)-1-(4-((1-(5-Ethoxy-2-fluorophenyl)piperidin-4-yl)oxy)phenyl)-3-methyl-4-(3-(methylsulfonyl)propoxy)pyrrolidin-2-yl)aceticacid

16A. 3-(Methylthio)propyl 4-methylbenzenesulfonate

A solution of 3-(methylthio)propan-1-ol (0.97 mL, 9.4 mmol), NEt₃ (2.0mL, 14 mmol), and N,N,N′,N′-tetramethyl-1,6-hexanediamine (0.20 mL, 0.94mmol) in toluene (9.4 mL) was cooled to 0° C. A solution of TsCl (2.69g, 14.1 mmol) in toluene (9.4 mL) was added dropwise. The reactionmixture was warmed to rt and stirred for 3 h. The reaction mixture wasdiluted with water and extracted with EtOAc. The combined organic layerswere washed with brine, dried (MgSO₄), and concentrated. The crudeproduct was purified by silica chromatography to provide 16A (2.17 g,8.31 mmol, 88% yield) as a colorless oil. LC-MS Anal. Calc'd forC₁₁H₁₆O₃S₂: 260.37, found [M+H] 261.0.

16B. 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate

To a solution of 16A (2.16 g, 8.31 mmol) in MeOH (44 mL) cooled to 0° C.was added a solution of OXONE® (10.2 g, 16.6 mmol) in water (44 mL). Theice bath was allowed to gradually warm to rt and the reaction mixturewas stirred for 3 h. The MeOH was removed under reduced pressure and thereaction mixture was diluted with water. The aqueous layer was extractedwith EtOAc (3×) and the combined organic layers were washed with brine,dried (MgSO₄), and concentrated to give 16B (2.39 g, 8.17 mmol, 98%yield) as a white solid. LC-MS Anal. Calc'd for C₁₁H₁₆O₅S₂: 292.37,found [M+H] 293.0.

Example 16 (8.4 mg) was prepared from 16B and 3C following the procedureof Example 1. LC-MS Anal. Calc'd for C₃₀H₄₁FN₂O₇S: 592.72, found [M+H]593.2. ¹H NMR (500 MHz, DMSO-d₆) δ 7.00 (t, J=10.5 Hz, 1H), 6.88 (d,J=7.4 Hz, 2H), 6.56-6.50 (m, 1H), 6.50-6.42 (m, 3H), 4.32-4.23 (m, 1H),4.00-3.91 (m, 2H), 3.75 (br. s, 1H), 3.60 (d, J 10.2 Hz, 1H), 3.54 (d, J6.6 Hz, 2H), 3.43-3.39 (m, 2H), 3.24 (br. s, 2H), 3.14 (br. s, 2H), 2.97(br. s, 3H), 2.92-2.81 (m, 2H), 2.61 (d, J=15.4 Hz, 1H), 2.48-2.41 (m,1H), 2.32-2.22 (m, 1H), 2.04-1.96 (m, 2H), 1.95-1.88 (m, 2H), 1.77-1.66(m, J=8.3 Hz, 2H), 1.32-1.26 (m, 3H), 0.94 (d, J=6.3 Hz, 3H). AnalyticalHPLC (Acquity): RT=1.7 min, HI: 100%. hGPR40 EC₅₀=980 nM.

Example 18, Isomer 1 and Isomer 22-((2S,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-isobutylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

18A. Ethyl 1-benzyl-3-isobutyl-4-oxopiperidine-3-carboxylate

To a solution of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate, HCl (9.27g, 31.1 mmol) in i-PrOH (31 mL) was added KOtBu (72 mL, 72 mmol) (1 M ini-PrOH) and 1-iodo-2-methylpropane (5.4 mL, 47 mmol). The reactionmixture was stirred at rt for 20 min and then at 75° C. for 12 h. Thereaction mixture was cooled to rt and poured into sat. aq. NH₄Cl. Theproduct was extracted with EtOAc, washed with brine, dried (Na₂SO₄), andconcentrated. The crude product was purified by silica chromatography togive 18A (4.70 g, 14.8 mmol, 48% yield) as a colorless oil. LC-MS Anal.Calc'd for C₁₉H₂₇NO₃: 317.42, found [M+H] 318.2. ¹H NMR (400 MHz, CDCl₃)δ 7.35-7.29 (m, 4H), 7.29-7.27 (m, 1H), 3.58 (s, 2H), 3.44 (dd, J=11.6,2.8 Hz, 1H), 3.07-2.93 (m, 1H), 2.92-2.78 (m, 1H), 2.47-2.33 (m, 2H),2.23 (d, J=11.4 Hz, 1H), 2.04 (s, 1H), 1.82-1.75 (m, 1H), 1.74-1.63 (m,1H), 1.45 (dd, J=13.9, 5.9 Hz, 1H), 1.30-1.22 (m, 4H), 0.88 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6 Hz, 3H).

18B. 1-Benzyl-3-isobutylpiperidin-4-one

To a flask with 18A (4.70 g, 14.8 mmol) was added 6 M aq. HCl (49 mL,300 mmol). The reaction mixture was stirred at 100° C. for 12 h. Thereaction mixture was cooled to rt and poured into 5 N NaOH/ice water andadditional 5 N NaOH was added until the pH ˜8. The reaction mixture wasdiluted with EtOAc, washed with water and brine, dried over Na₂SO₄, andconcentrated. The crude product was purified by silica chromatography toprovide 18B (2.11 g, 8.60 mmol, 58% yield) as a colorless oil. LC-MSAnal. Calc'd for C₁₆H₂₃NO: 245.36, found [M+H] 246.2. ¹H NMR (400 MHz,CDCl₃) δ 7.38-7.31 (m, 4H), 7.30-7.27 (m, 1H), 3.72-3.62 (m, 1H),3.60-3.50 (m, 1H), 3.05-2.91 (m, 2H), 2.63-2.46 (m, 3H), 2.44-2.35 (m,1H), 2.23 (dd, J=11.1, 9.4 Hz, 1H), 1.72 (ddd, J=13.9, 7.9, 6.2 Hz, 1H),1.59-1.45 (m, 1H), 1.09 (dt, J=13.8, 6.8 Hz, 1H), 0.87 (d, J=6.6 Hz,3H), 0.84 (d, J=6.6 Hz, 3H). 18C.(3,4-cis)-1-Benzyl-3-isobutylpiperidin-4-ol: To a solution of 18B (1.51g, 6.15 mmol) in THF (31 mL) at −78° C. was added a 1 M solution ofL-Selectride (9.2 mL, 9.2 mmol) in THF. The reaction mixture was stirredat −78° C. for 1.5 h and then quenched with 1 M aq. NaOH (9.2 mL, 9.2mmol) and warmed to rt. 30% Aq. H₂O₂(9.4 mL, 92 mmol) was added and thereaction mixture was stirred at rt for 0.5 h. The reaction mixture wasdiluted with EtOAc/water and the layers were separated. The aqueouslayer was extracted with EtOAc (2×). The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated. The crude productwas purified by silica chromatography to provide 18C (0.66 g, 2.7 mmol,43% yield) as a colorless oil. LC-MS Anal. Calc'd for C₁₆H₂₅NO: 247.38,found [M+H] 248.1. ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.28 (m, 4H),7.26-7.21 (m, 1H), 3.87 (br. s., 1H), 3.59-3.50 (m, 1H), 3.49-3.42 (m,1H), 2.55 (d, J=11.0 Hz, 1H), 2.47 (d, J=8.6 Hz, 1H), 2.41-2.28 (m, 1H),2.10 (t, J=10.7 Hz, 1H), 1.87-1.70 (m, 3H), 1.65-1.55 (m, 2H), 1.24-1.17(m, 2H), 0.87 (d, J=6.6 Hz, 6H).

18D. (3,4-cis)-3-Isobutylpiperidin-4-ol

To a solution 18C (0.66 g, 2.7 mmol) in MeOH (18 mL) was added 10% Pd/C(0.142 g, 0.133 mmol). The mixture was evacuated and purged with H₂ (3×)and then stirred under a H₂ balloon for 4 h. The reaction mixture wasfiltered through CELITE® and concentrated to give 18D (0.39 g, 2.480mmol, 93% yield) as a white solid. LC-MS Anal. Calc'd for C₉H₁₉NO:157.25, found [M+H] 158.1. ¹H NMR (400 MHz, CDCl₃) δ 3.93 (q, J=3.4 Hz,1H), 3.04-2.90 (m, 1H), 2.77 (dt, J=12.2, 4.1 Hz, 1H), 2.72-2.67 (m,2H), 1.76 (br. s., 2H), 1.74-1.67 (m, 3H), 1.67-1.57 (m, 1H), 1.24-1.08(m, 2H), 0.89 (d, J=6.6 Hz, 6H).

18E.(3,4-cis)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-isobutylpiperidin-4-ol

To a solution of 18D (320 mg, 2.04 mmol) and K₂CO₃ (1130 mg, 8.14 mmol)in DMSO (4.1 mL) was added 1J (475 mg, 2.14 mmol). The reaction mixturewas stirred at 110° C. for 1 h and then at 90° C. overnight. Thereaction mixture was diluted with EtOAc and the organic layer was washedwith water and brine, dried over Na₂SO₄, and concentrated. The crudeproduct was purified by silica chromatography to provide 18E (493 mg,1.65 mmol, 81% yield) as a colorless oil. LC-MS Anal. Calc'd forC₁₅H₂₃ClN₂O₂: 298.81, found [M+H] 299.1. ¹H NMR (400 MHz, CDCl₃) δ 7.93(s, 1H), 6.26 (s, 1H), 3.97 (d, J=3.3 Hz, 1H), 3.86 (s, 3H), 3.29-3.22(m, 1H), 3.19 (ddd, J=11.9, 3.9, 1.7 Hz, 1H), 3.06 (td, J=11.8, 3.1 Hz,1H), 2.77 (t, J=11.2 Hz, 1H), 1.99-1.88 (m, 2H), 1.88-1.80 (m, 1H), 1.70(br. s., 1H), 1.68-1.58 (m, 1H), 1.23-1.18 (m, 2H), 0.91 (d, J=4.0 Hz,3H), 0.89 (d, J=4.2 Hz, 3H).

Example 18, Isomer 1 and Isomer 2 were prepared from 18E following theprocedure of Example 2 followed by chiral SFC to separate the twoisomers. Example 18, Isomer 1 (19.4 mg). LC-MS Anal. Calc'd forC₃₁H₄₅ClN₄O₆: 605.17, found [M+]605.30. ¹H NMR (500 MHz, DMSO-d₆) δ 8.02(s, 1H), 7.43 (br. s., 1H), 7.04 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.8 Hz,1H), 6.43 (s, 1H), 4.72 (br. s., 1H), 3.81 (s, 3H), 3.73 (br. s., 1H),3.66-3.54 (m, 3H), 3.51-3.37 (m, 6H), 3.21 (s, 3H), 2.99-2.83 (m, 2H),2.58 (d, J=15.1 Hz, 2H), 2.36-2.23 (m, 1H), 2.17 (d, J=11.6 Hz, 1H),2.01-1.86 (m, 1H), 1.78-1.50 (m, 4H), 1.39 (t, J=10.9 Hz, 1H), 1.13 (d,J=9.1 Hz, 1H), 1.00-0.77 (m, 9H). Analytical HPLC (Acquity): RT=1.9 min,HI: 97.4%. hGPR40 EC₅₀=1300 nM. Example 18, Isomer 2 (19.2 mg). LC-MSAnal. Calc'd for C₃₁H₄₅ClN₄O₆: 605.17, found [M+] 605.30. ¹H NMR (500MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.52-7.33 (m, 1H), 7.11-6.96 (m, 1H),6.77-6.69 (m, 1H), 6.43 (s, 1H), 4.83-4.58 (m, 1H), 3.81 (s, 3H),3.74-3.70 (m, 1H), 3.63-3.44 (m, 4H), 3.41-3.30 (m, 5H), 3.21 (s, 3H),2.89 (s, 2H), 2.63-2.51 (m, 2H), 2.31-2.24 (m, 1H), 2.21-2.09 (m, 1H),2.00-1.86 (m, 1H), 1.77-1.68 (m, 2H), 1.65-1.57 (m, 2H), 1.46-1.31 (m,1H), 1.21-1.06 (m, 1H), 1.01-0.69 (m, 9H). Analytical HPLC (Acquity):RT=1.9 min, HI: 97.7%. hGPR40 EC₅₀=290 nM.

Example 19, Isomer 1 and Isomer 22-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-isobutylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 19, Isomer 1 and Isomer 2 were prepared from 4-iodophenolfollowing the procedure of Example 18. Example 19, Isomer 1 (12.6 mg).LC-MS Anal. Calc'd for C₃₂H₄₆ClN₃O₆: 604.18, found [M+] 604.3. ¹H NMR(500 MHz, DMSO-d₆) δ 8.02 (s, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.47 (d,J=8.3 Hz, 2H), 6.41 (s, 1H), 3.95-3.85 (m, 1H), 3.80 (s, 3H), 3.72 (br.s., 1H), 3.62-3.52 (m, 2H), 3.50-3.44 (m, 3H), 3.34-3.25 (m, 3H), 3.20(s, 3H), 2.95-2.83 (m, 1H), 2.65-2.52 (m, 3H), 2.26 (q, J=6.8 Hz, 1H),2.11-2.01 (m, 1H), 1.94-1.85 (m, 1H), 1.77-1.55 (m, 4H), 1.50 (t, J=10.6Hz, 1H), 1.26-1.15 (m, 2H), 0.93 (d, J=7.2 Hz, 3H), 0.88 (d, J=6.3 Hz,6H). Analytical HPLC (Acquity): RT=2.2 min, HI: 94.3%. hGPR40 EC₅₀=1500nM. Example 19, Isomer 2 (12.9 mg). LC-MS Anal. Calc'd for C₃₂H₄₆ClN₃O₆:604.18, found [M+] 604.4. ¹H NMR (500 MHz, DMSO-d₆) δ 8.02 (s, 1H), 6.87(d, J=8.0 Hz, 2H), 6.47 (d, J=8.0 Hz, 2H), 6.41 (s, 1H), 3.94-3.87 (m,1H), 3.80 (s, 3H), 3.72 (d, J=3.0 Hz, 1H), 3.61-3.41 (m, 6H), 3.34-3.28(m, 2H), 3.20 (s, 3H), 2.93-2.85 (m, 1H), 2.64-2.51 (m, 3H), 2.30-2.23(m, 1H), 2.08 (d, J=11.0 Hz, 1H), 1.88 (d, J=4.4 Hz, 1H), 1.77-1.55 (m,4H), 1.49 (t, J=10.9 Hz, 1H), 1.26-1.16 (m, 2H), 0.93 (d, J=6.9 Hz, 3H),0.88 (d, J=6.3 Hz, 6H). Analytical HPLC (Acquity): RT=2.2 min, HI:96.6%. hGPR40 EC₅₀=230 nM.

Example 202-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)-3-fluorophenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 20 (white solid, 43 mg) was prepared as a single isomer from2-fluoro-4-iodophenol following the procedure of Example 14. LC-MS Anal.Calc'd for C₃₁H₄₂F₂N₂O₆: 576.67, found [M+H] 577.3. ¹H NMR (400 MHz,CD₂Cl₂) δ 6.97-6.83 (m, 2H), 6.47 (dd, J=7.4, 3.0 Hz, 1H), 6.40-6.30 (m,2H), 6.27 (dd, J=8.8, 1.8 Hz, 1H), 3.94 (q, J=7.0 Hz, 2H), 3.73 (d,J=4.0 Hz, 2H), 3.62 (td, J=9.1, 4.2 Hz, 1H), 3.59-3.34 (m, 9H), 3.28 (s,3H), 2.85-2.73 (m, 1H), 2.67 (td, J=11.6, 2.5 Hz, 1H), 2.49 (dd, J=12.1,9.9 Hz, 1H), 2.45-2.36 (m, 1H), 2.12-1.99 (m, 2H), 1.87-1.71 (m, 3H),1.35 (t, J=7.0 Hz, 3H), 1.12 (d, J=6.6 Hz, 3H), 0.99 (d, J=7.0 Hz, 3H).Analytical HPLC (ZORBAX®, 0% B start): RT=8.5 min, HI: 100%. hGPR40EC₅₀=110 nM.

Example 21, Isomer 1 and Isomer 22-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxy-2-methylpropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 21 was prepared from 3-bromo-2-methylprop-1-ene following theprocedure of Example 1. The two isomers were separated by chiral SFC.Example 21, Isomer 1 (27.4 mg). LC-MS Anal. Calc'd for C₃₀H₄₂ClN₃O₆:576.12, found [M+] 576.3. ¹H NMR (500 MHz, DMSO-d₆) δ 8.01 (br. s., 1H),6.88 (d, J=7.7 Hz, 2H), 6.47 (d, J=7.7 Hz, 2H), 6.40 (br. s., 1H),3.92-3.83 (m, 1H), 3.80 (br. s., 3H), 3.70 (br. s., 1H), 3.59 (d, J=9.4Hz, 1H), 3.35-3.22 (m, 7H), 3.20 (br. s., 3H), 3.17 (br. s., 1H),2.88-2.80 (m, 1H), 2.69-2.61 (m, 1H), 2.60-2.52 (m, 1H), 2.27 (d, J=7.2Hz, 1H), 2.08 (d, J=12.1 Hz, 1H), 1.91 (d, J=6.1 Hz, 2H), 1.57 (d,J=11.0 Hz, 1H), 1.29-1.19 (m, 1H), 1.04 (d, J=5.8 Hz, 3H), 0.92 (d,J=6.3 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H). Analytical HPLC (Acquity): RT=2.0min, HI: 94.6%. hGPR40 EC₅₀=120 nM. The second isomer was repurified byRP-Prep. HPLC to provide Example 21, Isomer 2, TFA (26.8 mg). LC-MSAnal. Calc'd for C₃₀H₄₂ClN₃O₆: 576.12, found [M+] 576.3. ¹H NMR (500MHz, DMSO-d₆) δ 8.02 (br. s., 1H), 6.88 (d, J=7.2 Hz, 2H), 6.49 (d,J=7.4 Hz, 2H), 6.40 (br. s., 1H), 3.86 (br. s., 1H), 3.80 (br. s., 3H),3.71 (br. s., 1H), 3.43-3.23 (m, 8H), 3.21 (br. s., 3H), 3.17 (br. s.,1H), 2.87-2.81 (m, 1H), 2.69-2.53 (m, 3H), 2.26 (d, J=6.6 Hz, 1H), 2.08(d, J=12.4 Hz, 1H), 1.92 (d, J=4.7 Hz, 2H), 1.58 (d, J=10.7 Hz, 1H),1.05 (d, J=4.7 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H), 0.87 (d, J=5.0 Hz, 3H).Analytical HPLC (Acquity): RT=2.0 min, HI: 94.6%. hGPR40 EC₅₀=100 nM.

Example 222-((2S,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-5-fluoropyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetic acid

22A.2-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-3-fluoro-5-iodopyridine

To a solution of 1P, Isomer 1 (410 mg, 1.60 mmol) in DMF (7 mL) at 0° C.was added 60% NaH (96 mg, 2.4 mmol). The reaction mixture was stirred at0° C. for 10 min and then warmed to rt for 20 min. The reaction mixturewas recooled to 0° C. and 2,3-difluoro-5-iodopyridine (385 mg, 1.60 mmolwas added. The reaction mixture was warmed to rt and stirred for 105min. The reaction mixture was cooled to 0° C. and quenched with sat. aq.NH₄Cl. The reaction mixture was partitioned between EtOAc/water. Theaqueous phase was extracted with EtOAc (2×). The combined organicextracts were washed with water and brine, dried (MgSO₄), andconcentrated. The crude product was purified by silica chromatography togive 22A (532 mg, 1.11 mmol, 70% yield) as a beige solid. LC-MS Anal.Calc'd for C₁₇H₁₈ClFIN₃O₂: 477.70, found [M+H] 478.0. ¹H NMR (400 MHz,CDCl₃) δ 8.08 (d, J=1.8 Hz, 1H), 7.99 (s, 1H), 7.61 (dd, J=9.1, 1.9 Hz,1H), 6.28 (s, 1H), 4.91 (td, J=9.2, 4.4 Hz, 1H), 3.92 (s, 3H), 3.64-3.53(m, 2H), 3.01-2.90 (m, 1H), 2.68 (dd, J=12.3, 9.7 Hz, 1H), 2.34-2.19 (m,2H), 1.95-1.81 (m, 1H), 1.06 (d, J=6.6 Hz, 3H).

22B.((2R,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-5-fluoropyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanoland((2R,3S,4R)-1-(5-butoxy-6-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol

To a pressure vial containing 22A (72.8 mg, 0.153 mmol) was added 1H (31mg, 0.15 mmol), CuI (5.8 mg, 0.031 mmol) and NaOH (18.3 mg, 0.458 mmol),and n-BuOH (1 mL). The resulting suspension was bubbled with argon for 2min, sealed, and stirred at 90° C. for 16 h. The reaction mixture wascooled to rt, diluted with water, and extracted with CH₂Cl₂ (3×). Thecombined organic extracts were washed with brine, dried (MgSO₄), andconcentrated. The residue was purified by silica chromatography toprovide((2R,3S,4R)-1-(6-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-5-fluoropyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol(54 mg, 0.083 mmol, 54% yield) and((2R,3S,4R)-1-(5-butoxy-6-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol(˜13%) as an inseparable mixture.((2R,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-5-fluoropyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol.LC-MS Anal. Calc'd for C₂₇H₃₈ClFN₄O₅: 553.07, found [M+] 553.3.((2R,3S,4R)-1-(5-Butoxy-6-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol.LC-MS Anal. Calc'd for C₃₁H₄₇ClN₄O₆: 606.32, found [M+H] 607.3.

Example 22 (off-white solid, 22.1 mg) was prepared as a single isomerfrom the inseparable mixture of 22B following the procedure ofExample 1. LC-MS Anal. Calc'd for C₂₈H₃₈ClFN₄O₆: 581.08, found [M+]581.3. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.28 (d, J=2.6 Hz, 1H),6.77 (dd, J=12.3, 2.6 Hz, 1H), 6.28 (s, 1H), 4.76 (td, J=9.1, 4.1 Hz,1H), 3.90 (s, 3H), 3.76 (br. s., 1H), 3.73 (dd, J=8.3, 5.4 Hz, 1H),3.64-3.42 (m, 8H), 3.33 (s, 3H), 2.94 (t, J=10.5 Hz, 1H), 2.84-2.78 (m,2H), 2.71-2.61 (m, 1H), 2.45 (q, J=7.2 Hz, 1H), 2.33-2.18 (m, 2H),1.92-1.79 (m, 3H), 1.07 (d, J=6.8 Hz, 3H), 1.02 (d, J=7.3 Hz, 3H).Analytical HPLC (ZORBAX®, 50% B start): RT=7.3 min, HI: 96.3%. hGPR40EC₅₀=89 nM.

Example 232-((2S,3S,4R)-1-(5-Butoxy-6-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid, TFA

Example 23 (grey solid, 2.6 mg) was isolated as a byproduct as a singleisomer during the preparation of Example 22. LC-MS Anal. Calc'd forC₃₂H₄₇ClN₄O₇: 635.19, found [M+] 635.4. ¹H NMR (400 MHz, CDCl₃) δ 8.11(s, 1H), 7.21 (s, 1H), 6.88 (s, 1H), 6.30 (d, J=13.0 Hz, 1H), 4.90-4.76(m, 1H), 4.09 (br. s., 1H), 4.01 (s, 3H), 3.89-3.64 (m, 3H), 3.61-3.43(m, 5H), 3.34 (s, 3H), 3.30 (br. s., 1H), 3.23-3.02 (m, 1H), 2.99-2.68(m, 2H), 2.61-2.43 (m, 2H), 2.41-2.16 (m, 2H), 2.02-1.70 (m, 7H),1.58-1.42 (m, 2H), 1.13 (d, J=6.6 Hz, 3H), 1.05-0.97 (m, 6H). AnalyticalHPLC (ZORBAX®, 50% B start): RT=8.0 min, HI: 93.5%. hGPR40 EC₅₀=110 nM.

Example 242-((2S,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-5-(trifluoromethyl)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

24A. (3,4-trans)-1-Benzyl-3-methylpiperidin-4-ol

To a solution of 1-benzyl-3-methylpiperidin-4-one (27.0 g, 133 mmol) inMeOH (80 mL) and water (200 mL) was added phosphoric acid (10.0 mL, 146mmol) at −10° C. To this mixture, NaBH₄ (10.1 g, 266 mmol) was added inportions over a period of 1 h. The reaction mixture was slowly warmed tort and stirred overnight. The reaction mixture was cooled to 0° C. andbasified with 10% aq. NaOH (5 mL). The product was extracted with EtOAc(3×150 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated to give 24A (27.3 g, 133 mmol, 100% yield) as a brown gum.LC-MS Anal. Calc'd for C₁₃H₁₉NO: 205.30, found [M+H] 206.2. ¹H NMR (400MHz, CDCl₃) δ 7.36-7.28 (m, 4H), 7.26-7.21 (m, 1H), 3.48 (s, 2H),3.20-3.09 (m, 1H), 2.91-2.83 (m, 1H), 2.82-2.75 (m, 1H), 2.03 (td,J=11.8, 2.5 Hz, 1H), 1.94-1.85 (m, 1H), 1.76-1.68 (m, 1H), 1.67-1.57 (m,2H), 1.37 (d, J=5.0 Hz, 1H), 0.96 (d, J=6.0 Hz, 3H).

24B. (3,4-trans)-1-Benzyl-3-methylpiperidin-4-ol, Isomer 1 and Isomer 2

24A (37.0 g, 180 mmol) was purified by chiral SFC to provide 24B, Isomer1 and Isomer 2 as brown oils. 24B, Isomer 1 (16.0 g, 78.0 mmol, 43%yield). LC-MS Anal. Calc'd for C₁₃H₁₉NO: 205.30, found [M+H] 206.0. ¹HNMR (400 MHz, CDCl₃) δ 7.36-7.29 (m, 4H), 7.26-7.21 (m, 1H), 3.48 (s,2H), 3.15 (br. s., 1H), 2.91-2.83 (m, 1H), 2.79 (dt, J=11.0, 3.0 Hz,1H), 2.03 (td, J=11.8, 2.5 Hz, 1H), 1.90 (ddt, J=12.5, 4.5, 3.0 Hz, 1H),1.75-1.67 (m, 1H), 1.67-1.57 (m, 2H), 1.38 (br. s., 1H), 0.96 (d, J=6.0Hz, 3H). 24B, Isomer 2 (14.0 g, 68.2 mmol, 38% yield). LC-MS Anal.Calc'd for C₁₃H₁₉NO: 205.30, found [M+H] 206.2. ¹H NMR (400 MHz, CDCl₃)δ 7.35-7.29 (m, 4H), 7.26-7.22 (m, 1H), 3.48 (s, 2H), 3.14 (td, J=9.9,4.8 Hz, 1H), 2.91-2.83 (m, 1H), 2.79 (dt, J=10.9, 2.8 Hz, 1H), 2.03 (td,J=11.8, 2.5 Hz, 1H), 1.90 (ddt, J=12.4, 4.8, 2.9 Hz, 1H), 1.75-1.67 (m,1H), 1.67-1.56 (m, 3H), 0.95 (d, J=6.0 Hz, 3H).

24C. (3,4-trans)-3-Methylpiperidin-4-ol

To a solution of 24B, Isomer 2 (14.0 g, 68.2 mmol) in MeOH (150 mL) wasadded 10% Pd/C (3.63 g). The reaction mixture was stirred at rt under H₂(1 atm) overnight. The reaction mixture was filtered through CELITE® andthe filtrate was concentrated to give 24C (7.50 g, 65.1 mmol, 95% yield)as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 3.21 (td, J=10.1, 4.4Hz, 1H), 3.09 (ddt, J=12.6, 4.2, 2.4 Hz, 1H), 3.00 (ddd, J=12.7, 4.2,1.6 Hz, 1H), 2.62 (td, J=12.5, 2.8 Hz, 1H), 2.31-2.18 (m, 1H), 1.99-1.88(m, 1H), 1.48-1.31 (m, 2H), 0.97 (d, J=6.5 Hz, 3H).

24D.(3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol

To a solution of 24C (7.50 g, 65.1 mmol) in DMSO (50 mL) at 0° C. wasadded K₂CO₃ (14 g, 98 mmol). After stirring for 15 min, 1J (14.5 g, 65.1mmol) was added and the reaction mixture was heated to 110° C.overnight. The reaction mixture was cooled to rt and extracted withEtOAc (3×100 mL). The combined organic layers were dried (Na₂SO₄) andconcentrated. The crude product was purified by silica chromatography togive 24D (13.2 g, 51.4 mmol, 79% yield) as a brown oil. LC-MS Anal.Calc'd for C₁₂H₁₇ClN₂O₂: 256.73, found [M+H] 257.0. ¹H NMR (400 MHz,CDCl₃) δ 7.96 (s, 1H), 6.25 (s, 1H), 3.88 (s, 3H), 3.63-3.53 (m, 1H),3.49 (ddd, J=12.3, 4.0, 2.8 Hz, 1H), 3.34 (tt, J=9.7, 4.8 Hz, 1H), 2.76(td, J=11.8, 2.5 Hz, 1H), 2.43 (dd, J=12.0, 10.5 Hz, 1H), 2.08-2.01 (m,1H), 1.86-1.67 (m, 2H), 1.49 (d, J=5.5 Hz, 1H), 1.06 (d, J=7.0 Hz, 3H).

24E.2-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-5-iodo-3-(trifluoromethyl)pyridine

To a solution of 24D (220 mg, 0.857 mmol) in DMF (4 mL) at rt was added60% NaH (103 mg, 2.57 mmol) and the reaction mixture was stirred for 15min. 2-Chloro-5-iodo-3-(trifluoromethyl)pyridine (277 mg, 0.900 mmol)was added and the resulting mixture was stirred at 120° C. for 12 h. Thereaction was quenched with sat. aq. NaHCO₃ and extracted with EtOAc(3×25 mL). The combined organic extracts were washed with water (3×) andbrine, dried (Na₂S₂O₄), and concentrated to give the crude product.Purification via silica chromatography gave 24E (260 mg, 0.493 mmol, 58%yield) as a white oil. LC-MS Anal. Calc'd for C₁₈H₁₈ClF₃IN₃O₂: 527.71,found [M+H] 528.2. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.56-8.43 (m, 1H),8.19-8.07 (m, 1H), 7.96 (s, 1H), 6.30 (s, 1H), 4.98 (td, J=9.0, 4.3 Hz,1H), 3.86 (s, 3H), 3.52 (dt, J=12.2, 1.9 Hz, 2H), 2.95 (ddd, J=12.6,10.3, 2.9 Hz, 1H), 2.69 (dd, J=12.3, 9.2 Hz, 1H), 2.32 (dtd, J=12.7,4.6, 3.1 Hz, 1H), 2.27-2.13 (m, 1H), 1.93-1.77 (m, 1H), 1.06 (d, J=6.6Hz, 3H).

Example 24 (white solid, 14 mg) was prepared as a single isomer from 24Efollowing the procedure of Example 1. LC-MS Anal. Calc'd forC₂₉H₃₈ClF₃N₄O₆: 631.08, found [M+H] 631.3. ¹H NMR (400 MHz, CD₂Cl₂) δ7.95 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.20 (d, J=2.6 Hz, 1H), 6.29 (s,1H), 4.84 (td, J=8.8, 4.2 Hz, 1H), 3.86 (s, 3H), 3.77 (br. s., 2H),3.63-3.55 (m, 1H), 3.54-3.38 (m, 7H), 3.29 (s, 3H), 2.98-2.87 (m, 1H),2.76 (br. s., 2H), 2.66 (dd, J=12.2, 9.4 Hz, 1H), 2.45 (q, J=6.2 Hz,1H), 2.34-2.25 (m, 1H), 2.22-2.09 (m, 1H), 1.88-1.73 (m, 3H), 1.04 (d,J=6.6 Hz, 3H), 1.01 (d, J=7.0 Hz, 3H). Analytical HPLC: RT=12.5 min, HI:95.4%. hGPR40 EC₅₀=65 nM.

Example 252-((2S,3S,4R)-1-(6-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-5-methylpyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetic acid

Example 25 (yellow oil, 5 mg) was prepared as a single isomer from2-chloro-5-iodo-3-methylpyridine following the procedure of Example 24.LC-MS Anal. Calc'd for C₂₉H₄₁ClN₄O₆: 577.11, found [M+] 577.4. ¹H NMR(400 MHz, CD₂Cl₂) δ 7.93 (s, 1H), 7.36 (br. s., 1H), 6.89 (br. s., 1H),6.28 (s, 1H), 4.74 (td, J=9.0, 4.1 Hz, 1H), 3.85 (s, 3H), 3.77-3.69 (m,1H), 3.65 (d, J=6.4 Hz, 1H), 3.59-3.38 (m, 9H), 3.28 (s, 3H), 2.99-2.84(m, 2H), 2.64 (dd, J=12.2, 9.6 Hz, 1H), 2.36 (br. s., 1H), 2.32-2.23 (m,1H), 2.17 (s, 3H), 2.13-2.05 (m, 1H), 1.86-1.66 (m, 3H), 1.06-0.97 (m,6H). Analytical HPLC (ZORBAX®, 0% B start): RT=8.6 min, HI: 95.6%.hGPR40 EC₅₀=300 nM.

Example 262-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-2-fluorophenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 26 (colorless oil, 25 mg) was prepared as a single isomer from3-fluoro-4-iodophenol following the procedure of Example 1. LC-MS Anal.Calc'd for C₂₉H₃₉ClFN₃O₆: 580.09, found [M+] 580.4. ¹H NMR (500 MHz,CD₂Cl₂) δ 7.96 (s, 1H), 6.99 (t, J=9.1 Hz, 1H), 6.79-6.67 (m, 2H), 6.29(s, 1H), 3.93 (td, J=8.8, 4.1 Hz, 1H), 3.86 (s, 3H), 3.72-3.64 (m, 1H),3.57-3.48 (m, 5H), 3.47-3.42 (m, 3H), 3.31 (s, 3H), 3.24 (dd, J=10.5,6.6 Hz, 1H), 2.94-2.84 (m, 1H), 2.65 (dd, J=12.4, 9.4 Hz, 1H), 2.59 (dd,J=16.8, 5.5 Hz, 1H), 2.52 (dd, J=16.8, 2.5 Hz, 1H), 2.23-2.16 (m, 1H),2.16-2.09 (m, 2H), 1.87-1.74 (m, 3H), 1.18 (d, J=6.9 Hz, 3H), 1.10 (d,J=6.6 Hz, 3H). Analytical HPLC: RT=11.4 min, HI: 99.0%. hGPR40 EC₅₀=110nM.

Example 272-((2R,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)-2-fluorophenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 27 (yellow oil, 6.6 mg) was obtained as a minor byproduct as asingle isomer during the preparation of Example 26. LC-MS Anal. Calc'dfor C₂₉H₃₉ClFN₃O₆: 580.09, found [M+] 580.4. ¹H NMR (500 MHz, CD₂Cl₂) δ7.96 (br. s., 1H), 7.00 (t, J=9.4 Hz, 1H), 6.75-6.66 (m, 2H), 6.29 (s,1H), 4.18-4.10 (m, 1H), 3.92-3.87 (m, 2H), 3.86 (s, 3H), 3.71-3.67 (m,1H), 3.54-3.48 (m, 3H), 3.48-3.43 (m, 1H), 3.40-3.35 (m, 2H), 3.24 (s,3H), 2.99 (d, J=11.0 Hz, 1H), 2.92-2.78 (m, 1H), 2.69-2.61 (m, 1H),2.59-2.49 (m, 2H), 2.43 (dd, J=16.8, 8.0 Hz, 1H), 2.24-2.16 (m, 1H),2.15-2.07 (m, 1H), 1.84-1.73 (m, 3H), 1.10 (d, J=6.9 Hz, 3H), 1.07 (d,J=7.4 Hz, 3H). Analytical HPLC: RT=11.3 min, HI: 99.0%. hGPR40 EC₅₀=2000nM.

Example 282-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-((2-methoxyethoxy)methoxy)-3-methylpyrrolidin-2-yl)aceticacid

Example 28 (off-white foam, 8 mg) was prepared as a single isomer from2-methoxyethoxymethyl chloride following the procedure of Example 2.LC-MS Anal. Calc'd for C₂₉H₄₀ClN₃O₇: 578.10, found [M+] 578.4. ¹H NMR(400 MHz, CDCl₃) δ 7.97 (s, 1H), 6.90 (d, J=9.0 Hz, 2H), 6.63 (d, J=9.0Hz, 2H), 6.27 (s, 1H), 4.79 (d, J=1.1 Hz, 2H), 4.03 (dt, J=5.0, 2.4 Hz,1H), 3.89 (s, 3H), 3.81 (td, J=8.6, 4.1 Hz, 1H), 3.75-3.71 (m, 2H), 3.68(dt, J=8.8, 3.0 Hz, 1H), 3.60-3.55 (m, 2H), 3.55-3.45 (m, 4H), 3.40 (s,3H), 2.88-2.72 (m, 3H), 2.63 (dd, J=12.3, 9.2 Hz, 1H), 2.40-2.32 (m,1H), 2.22-2.08 (m, 2H), 1.87-1.76 (m, 1H), 1.14 (d, J=6.8 Hz, 3H), 1.08(d, J=7.3 Hz, 3H). Analytical HPLC: RT=9.4 min, HI: 99.0%. hGPR40EC₅₀=180 nM.

Example 292-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-ethoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid, TFA

Example 29 (brown solid, 45 mg) was prepared as a single isomer fromethyl iodide following the procedure of Example 1. LC-MS Anal. Calc'dfor C₃₀H₄₂ClN₃O₆: 576.12, found [M+] 576.2. ¹H NMR (400 MHz, DMSO-d₆) δ8.02 (s, 1H), 6.88 (d, J=9.0 Hz, 2H), 6.48 (d, J=9.0 Hz, 2H), 6.40 (s,1H), 3.86 (td, J=8.8, 4.0 Hz, 2H), 3.81 (s, 3H), 3.73 (d, J=5.0 Hz, 2H),3.62-3.57 (m, 3H), 3.51-3.43 (m, 3H), 3.42-3.31 (m, 4H), 2.94-2.80 (m,1H), 2.69-2.57 (m, 2H), 2.30-2.23 (m, 1H), 2.12-2.05 (m, 1H), 2.00-1.89(m, 1H), 1.72 (quin, J=6.4 Hz, 2H), 1.65-1.53 (m, 1H), 1.09 (t, J=7.0Hz, 3H), 1.05 (d, J=6.5 Hz, 3H), 0.94 (d, J=7.5 Hz, 3H). AnalyticalHPLC: RT=12.9 min, HI: 99.0%. hGPR40 EC₅₀=220 nM.

Example 302-((2S,3S,4R)-1-(6-((1-(5-Chloro-2-methoxypyridin-4-yl)piperidin-4-yl)oxy)-5-(trifluoromethyl)pyridin-3-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetic acid

Example 30 (white solid, 4 mg) was prepared from 4A following theprocedure of Example 24. LC-MS Anal. Calc'd for C₂₈H₃₆ClF₃N₄O₆: 617.06,found [M+] 617.3. ¹H NMR (400 MHz, CD₂Cl₂) δ 7.94 (s, 1H), 7.67 (d,J=2.6 Hz, 1H), 7.18 (d, J=3.1 Hz, 1H), 6.30 (s, 1H), 3.85 (s, 3H), 3.77(br. s., 2H), 3.58 (dt, J=9.0, 6.4 Hz, 1H), 3.53-3.42 (m, 5H), 3.41 (s,3H), 3.36-3.30 (m, 1H), 3.29 (s, 3H), 3.17-3.09 (m, 2H), 2.76 (br. s.,1H), 2.47-2.38 (m, 1H), 2.15-2.06 (m, 2H), 2.01-1.93 (m, 2H), 1.81(quin, J=6.2 Hz, 2H), 1.00 (d, J=7.3 Hz, 3H). Analytical HPLC: RT=11.8min, HI: 98.0%. hGPR40 EC₅₀=61 nM.

Example 312-((2S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-methoxypropoxy)-3,3-dimethylpyrrolidin-2-yl)aceticacid

31A. (R)-2-Benzyl 1-tert-butyl3,3-dimethyl-4-oxopyrrolidine-1,2-dicarboxylate

To a solution of (R)-2-benzyl 1-tert-butyl4-oxopyrrolidine-1,2-dicarboxylate (3.00 g, 9.39 mmol) in THF (35 mL) at−78° C., was added a 1 M solution of LiHMDS in THF (10.3 mL, 10.3 mmol).The reaction mixture was stirred at −78° C. for 1 h. MeI (2.9 mL, 47mmol) was added in one portion. The cold bath was removed and thereaction mixture was slowly warmed to rt and stirred for 2 h. Thereaction was quenched with sat. aq. NH₄Cl, diluted with EtOAc, washedwith water and brine, dried, and concentrated. The crude product waspurified by silica chromatography to give 31A (506 mg, 1.46 mmol, 16%yield) as a white foam. LC-MS Anal. Calc'd for C₁₉H₂₅NO₅: 347.41, found[M+H-Boc] 248.2. ¹H NMR (400 MHz, CDCl₃) δ 7.18 (br. s., 5H), 5.17-4.86(m, 2H), 4.34-4.11 (m, 1H), 3.98-3.72 (m, 2H), 1.33-1.20 (m, 9H),1.14-1.09 (m, 3H), 0.87-0.82 (m, 3H).

31B. (2R)-2-Benzyl 1-tert-butyl4-hydroxy-3,3-dimethylpyrrolidine-1,2-dicarboxylate

To a solution of 31A (500 mg, 1.44 mmol) in THF (5 mL) was added to asuspension of NaBH₄ (218 mg, 5.76 mmol) in MeOH (5 mL) at 0° C. Thereaction mixture was stirred at 0° C. for 1.5 h. The reaction wasquenched with sat. aq. NH₄Cl and diluted with EtOAc/water. The layerswere separated and the organic layer was washed with brine, dried(MgSO₄), and concentrated. The crude product was purified by silicachromatography to provide 31B (453 mg, 1.30 mmol, 90% yield) as acolorless oil. LC-MS Anal. Calc'd for C₁₉H₂₇NO₅: 349.42, found [M+H-Boc]250.2. ¹H NMR (400 MHz, CDCl₃) δ 7.48-7.29 (m, 5H), 5.42-5.06 (m, 2H),4.07-3.87 (m, 1H), 3.85-3.59 (m, 3H), 1.52-1.31 (m, 9H), 1.12 (d, J=4.4Hz, 3H), 1.03 (d, J=12.1 Hz, 3H).

Example 31 (white solid, 17 mg) was prepared as a single isomer from 31Bfollowing the procedure of Example 1. LC-MS Anal. Calc'd forC₃₀H₄₂ClN₃O₆: 576.12, found [M+] 576.5. ¹H NMR (500 MHz, methanol-d₄) δ7.91 (s, 1H), 6.88 (d, J=8.8 Hz, 2H), 6.52 (d, J=9.1 Hz, 2H), 6.36 (s,1H), 3.85 (s, 3H), 3.84-3.78 (m, 2H), 3.63 (dt, J=9.1, 6.1 Hz, 1H),3.55-3.47 (m, 5H), 3.45 (dt, J=9.1, 6.0 Hz, 1H), 3.41-3.37 (m, 2H), 3.32(s, 3H), 2.90-2.82 (m, 2H), 2.63 (dd, J=12.2, 9.7 Hz, 1H), 2.52 (dd,J=16.7, 2.3 Hz, 1H), 2.20-2.13 (m, 1H), 2.09-1.98 (m, 1H), 1.82 (quin,J=6.2 Hz, 2H), 1.75-1.65 (m, 1H), 1.16 (s, 3H), 1.13 (d, J=6.6 Hz, 3H),0.98 (s, 3H). Analytical HPLC (ZORBAX®, 0% B start): RT=8.6 min, HI:99.0%. hGPR40 EC₅₀=310 nM.

Example 322-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-cyanopropoxy)-3-methylpyrrolidin-2-yl)aceticacid

32A. (2R,3S,4R)-1-Benzyl 2-methyl4-(3-(methoxymethoxy)propoxy)-3-methylpyrrolidine-1,2-dicarboxylate

To a stirred solution of 1E (0.130 g, 0.370 mmol) in CH₂Cl₂ (3 mL), at−10° C., DIPEA (0.32 mL, 1.9 mmol) and chloromethyl methyl ether (0.070mL, 0.93 mmol) were added sequentially under nitrogen. The reactionmixture was warmed to rt and stirred overnight. The reaction mixture wasextracted with CH₂Cl₂ (2×), washed with sat. aq. NaHCO₃, water, andbrine, dried (Na₂SO₄), and concentrated. The crude product was purifiedby silica chromatography to give 32A (0.100 g, 0.253 mmol, 68% yield) asgummy oil. LC-MS Anal. Calc'd for C₂₀H₂₉NO₇: 395.45, found [M+H₂O]413.0. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.27 (m, 5H), 5.26-4.97 (m, 2H),4.71-4.56 (m, 2H), 4.13-3.94 (m, 1H), 3.74 (s, 3H), 3.61-3.53 (m, 4H),3.53-3.39 (m, 3H), 3.34 (d, J=3.5 Hz, 3H), 2.57-2.42 (m, 1H), 1.88-1.70(m, 2H), 1.13 (dd, J=7.0, 2.0 Hz, 3H).

32B.2-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-(methoxymethoxy)propoxy)-3-methylpyrrolidin-2-yl)aceticacid

32B was prepared from 32A following the procedure of Example 2. LC-MSAnal. Calc'd for C₃₀H₄₂ClN₃O₇: 592.12, found [M+] 592.4. ¹H NMR (400MHz, DMSO-d₆) δ 12.20 (br. s., 1H), 8.01 (s, 1H), 6.92-6.85 (m, 2H),6.48 (d, J=9.0 Hz, 2H), 6.40 (s, 1H), 4.56-4.50 (m, 2H), 3.86 (td,J=8.9, 4.3 Hz, 1H), 3.81 (s, 3H), 3.73 (d, J=4.0 Hz, 1H), 3.60 (d, J=7.5Hz, 1H), 3.56-3.42 (m, 6H), 3.42-3.34 (m, 2H), 3.27-3.20 (m, 3H),2.94-2.78 (m, 1H), 2.75-2.56 (m, 2H), 2.32-2.21 (m, 1H), 2.15-2.02 (m,1H), 2.00-1.91 (m, 2H), 1.76 (quin, J=6.3 Hz, 2H), 1.65-1.51 (m, 1H),1.05 (d, J=6.5 Hz, 3H), 0.94 (d, J=7.5 Hz, 3H).

32C. Ethyl2-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-hydroxypropoxy)-3-methylpyrrolidin-2-yl)acetate

To a solution of 32B (0.035 g, 0.059 mmol) in EtOH (2 mL) was addedH₂SO₄ (0.032 mL, 0.59 mmol). The reaction mixture was heated to 80° C.for 2 h. The reaction mixture was diluted with water and extracted withEtOAc (3×). The combined organic extracts were dried (Na₂SO₄) andconcentrated. The crude product was purified by silica chromatography togive 32C (0.017 g, 0.030 mmol, 50% yield) as a brown gummy oil. LC-MSAnal. Calc'd for C₃₀H₄₂ClN₃O₆: 576.12, found [M+] 576.4.

32D. Ethyl2-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-3-methyl-4-(3-((methylsulfonyl)oxy)propoxy)pyrrolidin-2-yl)acetate

To a solution of 32C (0.015 g, 0.026 mmol) in CH₂Cl₂ (10 mL) at 0° C.was added NEt₃ (11 μl, 0.078 mmol), MsCl (4.1 μl, 0.052 mmol), and DMAP(3.2 μg, 0.026 μmol). The reaction mixture was stirred at 0° C. for 1 h.The reaction mixture was diluted with water and extracted with CH₂Cl₂.The organic layer was washed with 1.5 N aq. HCl, 10% aq. NaHCO₃, andbrine, dried (Na₂SO₄), and concentrated to give 32D (0.016 g, 0.024mmol, 94% yield) as a brown oil, which was used without furtherpurification. LC-MS Anal. Calc'd for C₃₁H₄₄ClN₃O₈S: 654.21, found [M+]654.2.

32E. Ethyl2-((2S,3S,4R)-1-(4-(((3,4-trans)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-(3-cyanopropoxy)-3-methylpyrrolidin-2-yl)acetate

To a solution of 32D (0.016 g, 0.024 mmol) in DMSO (10 mL) was addedNaCN (0.012 g, 0.25 mmol). The reaction mixture was heated to 50° C.overnight. The reaction mixture was diluted with water and extractedwith EtOAc (3×). The combined organic layers were washed with brine,dried (Na₂SO₄), and concentrated to give 32E (0.0080 g, 0.014 mmol, 56%yield) as a brown oil. LC-MS Anal. Calc'd for C₃₁H₄₁ClN₄O₅: 585.13,found [M+] 585.2.

Example 32 (brown solid, 15 mg) was prepared from 32E following theprocedure of Example 1. LC-MS Anal. Calc'd for C₃₁H₄₁ClN₄O₅: 585.13,found [M+] 585.2. ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 6.88 (d,J=9.0 Hz, 2H), 6.48 (d, J=9.0 Hz, 2H), 6.40 (s, 1H), 3.86 (td, J=8.9,4.3 Hz, 1H), 3.81 (s, 3H), 3.76 (d, J=4.5 Hz, 1H), 3.61 (d, J=10.5 Hz,1H), 3.56-3.48 (m, 2H), 3.47 (d, J=3.5 Hz, 1H), 3.44 (d, J=2.5 Hz, 1H),3.42-3.38 (m, 1H), 3.35 (br. s., 2H), 2.86 (t, J=10.3 Hz, 1H), 2.71-2.56(m, 2H), 2.55-2.52 (m, 1H), 2.47-2.38 (m, 1H), 2.28 (q, J=7.4 Hz, 1H),2.14-2.02 (m, 1H), 2.00-1.87 (m, 1H), 1.86-1.74 (m, 2H), 1.68-1.49 (m,1H), 1.05 (d, J=6.5 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H). Analytical HPLC (25min gradient): RT=18.9 min, HI: 97.0%. hGPR40 EC₅₀=190 nM.

Example 33 2-((2S,3S,4R)-1-(2-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyrimidin-5-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)aceticacid

33A. (2R,3S,4R)-Benzyl2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyrrolidine-1-carboxylate

To a stirring suspension of((2R,3S,4R)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol (0.950g, 4.67 mmol) and sodium bicarbonate (0.491 g, 5.84 mmol) in a mixedsolvent of DCM (10 mL) and water (10 mL) at rt was added benzylcarbonochloridate (0.843 mL, 5.61 mmol) dropwise over 5 min. Afteraddition, the mixture was vigorously stirred at rt for 1 h, LC-MS showedthe reaction was not complete. About 0.2 mL of benzyl chloroformate wasadded. After stirring for one more hour, the reaction was quenched withwater. The mixture was extracted with EtOAc (3×). The combined organicextracts were washed with water and brine, dried (MgSO₄) andconcentrated. The crude product was purified by flash chromatographyeluting with hexane/EtOAc (0%-50%, 20 min; 50%, 10 min; 50-100%, 15 min;100%, 10 min). The desired fractions were pooled, concentrated and driedin vacuum to afford 33A (0.954 g, 2.80 mmol, 60% yield) as a colorlessoil, LC-MS Anal. Calc'd for C₁₈H₂₇NO₅: 337.19, found [M+H] 338.1. ¹H NMR(400 MHz, CDCl₃) δ 7.43-7.32 (m, 5H), 5.20-5.14 (m, 2H), 4.43 (dd,J=7.9, 3.1 Hz, 1H), 3.86-3.76 (m, 2H), 3.71-3.64 (m, 1H), 3.59-3.50 (m,3H), 3.48-3.42 (m, 2H), 3.34 (s, 2H), 2.06-1.96 (m, 1H), 1.83 (quin,J=6.1 Hz, 2H), 1.14-1.07 (m, 3H), 1.16-1.07 (m, 3H).

33B. (2R,3S,4R)-Benzyl4-(3-methoxypropoxy)-3-methyl-2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

To a stirring solution of 33A (0.954 g, 2.83 mmol) in DCM (12 mL) cooledat 0° C. was added Et₃N (0.788 mL, 5.65 mmol), followed bymethanesulfonyl chloride (0.330 mL, 4.24 mmol) dropwise over 5 min.After addition, the resulting cloudy solution was stirred at 0° C. for 1h. LC-MS showed the reaction was complete. The reaction mixture wasdiluted with EtOAc, washed with water (2×), sat. aq. NaHCO₃, brine,dried (MgSO₄) and concentrated. The obtained oily residue was dried inhigh vacuum to afford 33B as an oily residue which was used inexperiment 35C immediately.

33C. (2S,3 S,4R)-Benzyl2-(cyanomethyl)-4-(3-methoxypropoxy)-3-methylpyrrolidine-1-carboxylate

To a solution of 33B in DMSO (9 mL) was added NaCN (555 mg, 11.32 mmol).After addition, the mixture was stirred at 50° C. After stirring for 16h, LC-MS showed the reaction was complete. The reaction was allowed tocool to rt, then quenched with water. The mixture was extracted withEtOAc (3×). The combined extracts were washed with water (2×), brine,dried (MgSO₄) and concentrated to dryness. The crude product waspurified by flash chromatography eluting with EtOAc/hexanes (0-60%, 15min; 60%, 10 min; 60-100%, 10 min) to afford 35C (830 mg, 2.372 mmol,84% yield) as a colorless oil. LC-MS Anal. Calc'd for C₁₉H₂₆N₂O₄:346.189, found [M+H] 347.1. ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.32 (m, 5H),5.30-5.06 (m, 2H), 3.85-3.41 (m, 8H), 3.35 (s, 3H), 3.04-2.71 (m, 2H),2.53-2.34 (m, 1H), 1.84 (quin, J=6.2 Hz, 2H), 1.19-0.96 (m, 3H).

33D. 2-((2S,3S,4R)-4-(3-Methoxypropoxy)-3-methylpyrrolidin-2-yl)acetonitrile

To a solution of 33C (430 mg, 1.241 mmol) in EtOAc (25 mL) was addedPd/C (210 mg, 0.099 mmol) (5% dry basis, Degussa type). After purgingwith hydrogen (3×), the suspension was vigorously stirred at rt under ahydrogen balloon for 16 h. LC-MS showed the reaction was complete. Themixture was filtered and the collected catalyst washed with EtOAc. Thefiltrate was concentrated to dryness, dried in high vacuum for 30 min toafford 35D (251 mg, 1.123 mmol, 90% yield) as a pale yellow oil. LC-MSAnal. Calc'd for C₁₁H₂₀N₂O₂: 212.152, found [M+H] 213.4. ¹H NMR (400MHz, CDCl₃) δ 3.48 (m, 1H), 3.43-3.34 (m, 4H), 3.29-3.22 (m, 4H),3.09-3.01 (m, 1H), 2.99-2.85 (m, 2H), 2.58-2.37 (m, 2H), 1.88-1.69 (m,3H), 1.05-1.01 (m, 3H).

33E.5-Bromo-2-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyrimidine

To a stirring solution of(3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-ol (350mg, 1.363 mmol) in DMF (6 mL) cooled at 0° C. was added NaH (60% inmineral oil) (82 mg, 2.045 mmol) in one portion. The resultingsuspension was stirred at 0° C. for 10 min, then at rt for 20 min. Theresulting pale yellow solution was cooled again at 0° C.,5-bromo-2-chloropyrimidine (264 mg, 1.363 mmol) was added. The resultingbrownish mixture was stirred at rt. LC-MS showed the reaction was notcomplete after 1.5 h. The reaction was allowed to continue stirring atrt overnight, then at 50° C. for 4 more h. The reaction mixture wascooled at 0° C., quenched by addition of sat. aq. NH₄Cl solution. Themixture was partitioned between EtOAc and water. The separated aqueousphase was extracted with EtOAc (2×). The combined extracts were washedwith brine, dried (MgSO₄) and concentrated. The crude was purified byflash chromatography eluting with EtOAc/hexanes (0-20%, 20 min; 20%, 5min; 20-40%, 10 min). The desired fractions were pooled, concentratedand dried in high vacuum to afford 33E (205 mg, 0.496 mmol, 36.3% yield)as a white solid. LC-MS Anal. Calc'd for C₁₆H₁₈BrClN₄O₂: 412.03, found[M+H] 412.9, 414.9 (bromine isotopes).

33F. 2-((2S,3S,4R)-1-(2-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)pyrimidin-5-yl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetonitrile

A reaction mixture of 33E (35 mg, 0.085 mmol), 35D (21.55 mg, 0.102mmol), (2-biphenyl)di-tert-butylphosphine (5.05 mg, 0.017 mmol), sodiumtert-butoxide (9.76 mg, 0.102 mmol) and Pd₂(dba)₃ (3.87 mg, 4.23 μmol)was stirred at 75° C. under argon for 16 h. LC-MS showed the reactionwas not complete. Additional amount of Pd₂(dba)₃ (3.87 mg, 4.23 μmol)and (2-biphenyl)di-tert-butylphosphine (5.05 mg, 0.017 mmol) were addedto the reaction mixture, which was heated at 110° C. for 4 more hours.After cooling to rt, the reaction mixture was diluted with water,extracted with DCM (3×). The combined organics were washed with brine,dried (MgSO₄) and concentrated to give a dark oily residue. The crudeproduct was purified by flash chromatography eluting with EtOAc/hexanes(0-30%, 15 min; 30%, 8 min; 30-50%, 10 min, 50%, 15 min). The desiredfractions were pooled, concentrated to dryness to afford 33F (11 mg, 60%pure) as a glassy residue. LC-MS showed the product was contaminatedwith an oxidized (2-biphenyl)di-tert-butylphosphine (about 2:3 ratio tothe desired product). LC-MS Anal. Calc'd for C₂₇H₃₇ClN₆O₄: 544.256,found [M+H] 545.3.

Example 33

To a microwave vial containing 33F (6 mg, 0.011 mmol) was added EtOH(0.2 mL) and 6 M solution of KOH (0.037 mL, 0.220 mmol). The reactionvial was sealed and stirred at 120° C. for 2.5 h. LC-MS showed thereaction was complete. The reaction was allowed to cool to rt andconcentrated to remove most of the EtOH. The remaining aqueous phase wasadjusted to pH=6 with 1 N aq. HCl, then extracted with DCM (3×). Thecombined extracts were washed with brine, dried (MgSO₄) and concentratedto dryness to give the crude product which was purified by prep HPLC.The desired fractions were pooled and concentrated to remove thevolatiles. The remaining aqueous suspension was neutralized with sat.aq. NaHCO₃ to pH=6, then extracted with DCM (3×). The DCM extracts werewashed with brine, dried (MgSO₄) and concentrated to give a glassyresidue, which was lyophilized in AcCN/water to afford the desiredproduct Example 35 (2.05 mg, 3.63 μmol, 33.0% yield) as an off-whitelyophilate. LC-MS Anal. Calc'd for C₂₇H₃₈ClN₅O₆: 563.251, found [M+H]564.3. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (m, 3H), 6.21 (s, 1H), 4.63 (d,J=4.0 Hz, 1H), 3.82 (s, 3H), 3.71 (d, J=3.1 Hz, 2H), 3.61-3.34 (m, 8H),3.31-3.22 (m, 3H), 2.95-2.80 (m, 1H), 2.78-2.67 (m, 2H), 2.58 (s, 1H),2.40 (d, J=7.3 Hz, 1H), 2.31-2.09 (m, 2H), 1.79 (dt, J=12.3, 6.1 Hz,4H), 1.01 (d, J=6.6 Hz, 3H), 0.96 (d, J=7.3 Hz, 3H). hGPR40 EC₅₀=101 nM.

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or asolvate thereof, wherein: X is independently selected from: a bond, O,S, NH, N(C₁₋₄ alkyl), CH₂, CH₂CH₂, CH(C₁₋₄ alkyl), OCH₂, CH₂O, OCH₂CH₂,and CH₂CH₂O; ring A is independently

ring B is independently a 4- to 7-membered saturated heterocyclecontaining carbon atoms, the nitrogen atom shown in the ring B and 0-1additional heteroatom selected from N, O, and S; and ring B issubstituted with 0-4 R²; R¹ is independently

phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containingcarbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S;wherein said phenyl, benzyl, naphthyl and heteroaryl are eachsubstituted with 0-3 R⁶; R², at each occurrence, is independentlyselected from: ═O, OH, halogen, C₁₋₆ alkyl substituted with 0-1 R¹²,C₁₋₆ alkoxy substituted with 0-1 R¹², C₁₋₄ haloalkyl substituted with0-1 R¹², C₁₋₄ haloalkoxy substituted with 0-1 R¹², —(CH₂)_(m)—C₃₋₆carbocycle substituted with 0-1 R¹², and —(CH₂)_(m)-(5- to 10-memberedheteroaryl containing carbon atoms and 1-4 heteroatoms selected from N,NR¹¹, O, and S); wherein said heteroaryl is substituted with 0-1 R¹²;when two R² groups are attached to two different carbon atoms, they maycombine to form a 1- to 3-membered carbon atom bridge over ring B; whentwo R² groups are attached to the same carbon, they may combine,together with the carbon atom to which they are attached, to form a 3-to 6-membered carbon atom containing spiro ring; R³ is independentlyselected from: C₁₋₆ alkyl substituted with R¹⁰, C₂₋₆ alkenyl substitutedwith R¹⁰, C₂₋₆ alkynyl substituted with R¹⁰, C₁₋₄ haloalkyl substitutedwith R¹⁰, —O(CH₂)₁₋₂O(CH₂)₁₋₄ R¹⁰, OR⁹, SR⁹, C(O)OR⁹, CO₂R⁹, S(O)R⁹,SO₂R⁹, and CONHR⁹; R⁴ and R^(4a) are independently selected from: H,halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle; R⁵, ateach occurrence, is independently selected from: halogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; R⁶, at each occurrence, isindependently selected from: halogen, OH, C₁₋₄ alkylthio, CN, SO₂(C₁₋₂alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₈ alkylsubstituted with 0-1 R⁷, C₁₋₆ alkoxy substituted with 0-1 R⁷,—(O)_(n)—(CH₂)_(m)—(C₃₋₁₀ carbocycle substituted with 0-2 R⁷), and—(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4heteroatoms selected from N, NR¹¹, O, and S); wherein said heteroaryl issubstituted with 0-2 R⁷; R⁷, at each occurrence, is independentlyselected from: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, SO₂(C₁₋₂ alkyl), and phenyl; R⁸ is independentlyselected from: H and C₁₋₄ alkyl; R⁹, at each occurrence, isindependently selected from: C₁₋₆ alkyl substituted with substitutedwith R¹⁰, and C₁₋₄ haloalkyl substituted with R¹⁰; R¹⁰, at eachoccurrence, is independently selected from: CN, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and tetrazolyl; R¹¹, ateach occurrence, is independently selected from: H, C₁₋₄ alkyl andbenzyl; R¹², at each occurrence, is independently selected from: OH,halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,CO₂(C₁₋₄ alkyl), and tetrazolyl; m, at each occurrence, is independently0, 1, or 2; and n, at each occurrence, is independently 0 or
 1. 2. Acompound according to claim 1, wherein R⁴ is hydrogen and R⁸ ishydrogen, further characterized by Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or asolvate thereof, wherein: X is independently selected from: O, N(CH₃),CH₂, CH₂O, and CH₂CH₂O; ring A is independently

ring B is independently a 4- to 7-membered saturated heterocyclecontaining carbon atoms and the nitrogen atom shown in ring B; and ringB is substituted with 0-4 R²; R¹ is independently

phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containingcarbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S;wherein said phenyl, benzyl, naphthyl and heteroaryl are eachsubstituted with 0-3 R⁶; R², at each occurrence, is independentlyselected from: ═O, OH, halogen, C₁₋₄ alkyl substituted with 0-1 R¹²,C₁₋₄ alkoxy substituted with 0-1 R¹², C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,and benzyl; when two R² groups are attached to two different carbonatoms, they may combine to form a 1- to 3-membered carbon atom bridgeover ring B; when two R² groups are attached to the same carbon, theymay combine, together with the carbon atom to which they are attached,to form a 3- to 6-membered carbon atom containing spiro ring; R³ isindependently selected from: C₁₋₄ alkyl substituted with R¹⁰, C₁₋₄alkoxy substituted with R¹⁰, C₁₋₄ haloalkyl substituted with R¹⁰, C₁₋₄haloalkoxy substituted with R¹⁰, OR⁹, and —O(CH₂)₁₋₂O(CH₂)₁₋₄ R¹⁰;R^(4a) is independently selected from: H, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle; R⁵, at each occurrence, isindependently selected from: halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, andC₁₋₆ haloalkoxy; R⁶, at each occurrence, is independently selected from:halogen, OH, C₁₋₄ alkylthio, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₁₋₈ alkyl substituted with 0-1 R⁷, C₁₋₄alkoxy substituted with 0-1 R⁷, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ carbocyclesubstituted with 0-2 R⁷), —(CH₂)_(m)-(naphthyl substituted with 0-2 R⁷),and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and1-4 heteroatoms selected from N, O, and S; wherein said heteroaryl issubstituted with 0-2 R⁷); R⁷, at each occurrence, is independentlyselected from: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, SO₂(C₁₋₂ alkyl), and phenyl; R⁹, at eachoccurrence, is independently selected from: C₁₋₆ alkyl substituted withsubstituted with R¹⁰, and C₁₋₄ haloalkyl substituted with R¹⁰; R¹⁰, ateach occurrence, is independently selected from: CN, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and tetrazolyl; R¹¹, ateach occurrence, is independently selected from: H, C₁₋₄ alkyl andbenzyl; R¹², at each occurrence, is independently selected from:halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,CO₂(C₁₋₄ alkyl), and tetrazolyl; m, at each occurrence, is independently0, 1, or 2; and n, at each occurrence, is independently 0 or
 1. 3. Acompound according to claim 2, wherein: ring A is independently

ring B is independently selected from:

R¹ is independently

phenyl substituted with 0-3 R⁶ or a heteroaryl substituted with 0-2 R⁶;wherein said heteroaryl is selected from: furanyl, oxazolyl, thiazolyl,pyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,

R², at each occurrence, is independently selected from: OH, halogen,C₁₋₄ alkyl substituted with 0-1 R¹², C₁₋₄ alkoxy substituted with 0-1R¹², and benzyl; R³ is independently selected from: C₁₋₄ alkylsubstituted with 1 R¹⁰, C₁₋₄ alkoxy substituted with 1 R¹⁰, C₁₋₄haloalkyl substituted with 1 R¹⁰, OR⁹, and C₁₋₄ haloalkoxy substitutedwith 1 R¹⁰; R^(4a) is independently selected from: H, halogen C₁₋₄alkyl, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl; R⁶, at each occurrence, isindependently selected from: halogen, OH, C₁₋₆ alkyl substituted with0-1 OH, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₃₋₆ cycloalkyl substituted with0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl,—O—C₃₋₆ cycloalkyl, benzyl, and oxazolyl; R⁹, at each occurrence, isindependently selected from: C₁₋₆ alkyl substituted with substitutedwith R¹⁰, and C₁₋₄ haloalkyl substituted with R¹⁰; R¹⁰, at eachoccurrence, is independently selected from: CN, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and tetrazolyl; and R¹²,at each occurrence, is independently selected from: halogen, CN, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₂ alkyl),and tetrazolyl.
 4. A compound according to claim 3, wherein: R¹ isindependently

phenyl substituted with 0-3 R⁶, or a heteroaryl substituted with 0-2 R⁶;wherein said heteroaryl is selected from: thiazolyl, pyridinyl,pyrimidinyl, pyrazinyl,


5. A compound according to claim 4, wherein: ring B is independentlyselected from:

R¹ is independently phenyl substituted with 0-3 R⁶, pyridinylsubstituted with 0-2 R⁶, pyrazinyl substituted with 0-2 R⁶, pyrimidinylsubstituted with 0-2 R⁶, thiazolyl substituted with 0-2 R⁶,

and R², at each occurrence, is independently selected from: OH, halogen,C₁₋₄ alkyl substituted with 0-1 CN, C₁₋₄ alkoxy, benzyl, andtetrazolylmethyl.
 6. A compound according to claim 5, wherein: ring B isindependently selected from:

R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶or pyridinyl substituted with 0-2 R⁶; R², at each occurrence, isindependently selected from: halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy andtetrazolylmethyl; R³, at each occurrence, is independently selectedfrom: C₁₋₄ alkyl substituted with R¹⁰, C₁₋₄ alkoxy substituted with R¹⁰,OR⁹, and —O(CH₂)₁₋₂O(CH₂)₁₋₄ R¹⁰; R⁶, at each occurrence, isindependently selected from: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl, and benzyl;R⁹, at each occurrence, is independently selected from: C₁₋₆ alkylsubstituted with substituted with R¹⁰, and C₁₋₄ haloalkyl substitutedwith R¹⁰; and R¹⁰, at each occurrence, is independently selected from:CN, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), andtetrazolyl.
 7. A compound of Formula (III), (IIIa), (IIIb) or (IIIc):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or asolvate thereof, wherein: R¹, at each occurrence, is independentlyphenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶; R²,at each occurrence, is independently selected from: halogen, C₁₋₄ alkyl,and C₁₋₄ alkoxy; R³, at each occurrence, is independently selected from:C₁₋₄ alkyl substituted with C₁₋₄ alkoxy, and C₁₋₄ alkoxy substitutedwith C₁₋₄ alkoxy; R^(4a), at each occurrence, is independently selectedfrom: H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, and cyclopropyl; R⁵, at eachoccurrence, is independently selected from: halogen and C₁₋₄ haloalkyl;and R⁶, at each occurrence, is independently selected from: halogen,C₁₋₆ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄alkyl, and C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl.
 8. Acompound of claim 7, wherein: R¹, at each occurrence, is independentlyphenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶; R²,at each occurrence, is independently selected from: halogen and C₁₋₂alkyl; R³, at each occurrence, is independently selected from: C₁₋₄alkyl substituted with C₁₋₄ alkoxy, and C₁₋₄ alkoxy substituted withC₁₋₄ alkoxy; R^(4a), at each occurrence, is independently selected from:H and methyl; R⁵, at each occurrence, is independently selected from:halogen and C₁₋₄haloalkyl; and R⁶, at each occurrence, is independentlyselected from: halogen, C₁₋₆ alkyl, and C₁₋₄ alkoxy.
 9. A compoundselected from:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or asolvate thereof.
 10. A compound of claim 1, having the structure:

or a stereoisomer, a pharmaceutically acceptable salt or a solvatethereof.
 11. A compound of claim 9, having the structure:

or a pharmaceutically acceptable salt or a solvate thereof.
 12. Acompound of claim 1, having the structure:

or a stereoisomer, a pharmaceutically acceptable salt or a solvatethereof.
 19. A compound of claim 1, having the structure:

or a stereoisomer, a pharmaceutically acceptable salt or a solvatethereof.
 20. A compound having the structure:

or a stereoisomer, a pharmaceutically acceptable salt or a solvatethereof.
 21. A compound having the structure:

or a stereoisomer, a pharmaceutically acceptable salt or a solvatethereof.
 22. A compound having the structure:

or a stereoisomer, a pharmaceutically acceptable salt or a solvatethereof.
 9. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 10. The pharmaceuticalcomposition according to claim 9, further comprising one or more othersuitable therapeutic agents selected from: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents,anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents,anti-pancreatic agents, lipid lowering agents, anorectic agents, andappetite suppressants.
 11. The pharmaceutical composition according toclaim 9, further comprising a dipeptidyl peptidase-IV inhibitor and/or asodium-glucose transporter-2 inhibitor.
 12. A method for the treatmentof a disease or disorder selected from diabetes, hyperglycemia, impairedglucose tolerance, gestational diabetes, insulin resistance,hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidneydisease, acute kidney injury, cardiorenal syndrome, acute coronarysyndrome, delayed wound healing, atherosclerosis and its sequelae,abnormal heart function, congestive heart failure, myocardial ischemia,stroke, Metabolic Syndrome, hypertension, obesity, fatty liver disease,dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low high-density lipoprotein (HDL), highlow-density lipoprotein (LDL), non-cardiac ischemia, pancreatitis, lipiddisorders, NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-AlcoholicFatty Liver Disease), liver cirrhosis; comprising administering to apatient in need of such treatment a therapeutically effective amount ofa compound of claim 1, or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt or a solvate thereof.